Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Hydroxy Group Directed Catalytic Hydrosilylation of Amides Jizhi Ni,† Tsubasa Oguro,† Taka Sawazaki, Youhei Sohma,* and Motomu Kanai* Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Downloaded via UNIV OF VIRGINIA on November 13, 2018 at 00:37:50 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
S Supporting Information *
ABSTRACT: Chemo- and site-selective hydrosilylation of αor β-hydroxy amides using organocatalyst B(C6F5)3 and commercially available hydrosilanes is described. This transformation is operative under mild conditions and tolerates a wide range of functional groups. The reaction was applied for selective reduction of a specific amide group of the therapeutically important cyclic peptide cyclosporin A, demonstrating the potential usefulness of this catalytic method in late-stage structural transformations of drug lead molecules.
H
Herein, we describe a new strategy for chemo- and siteselective reduction of α- or β-hydroxy amides using commercially available organocatalyst B(C6F5)3 and hydrosilanes (Scheme 1). This hydrosilylation method efficiently reduces both tertiary and secondary amide (peptide) bonds with high functional group tolerance under very mild conditions.
ydroxy amines are important structural motifs in various biologically active compounds, including drugs (Figure 1).1 Due to the ready availability of amides, reduction of
Scheme 1. Strategy for OH-Directed Selective Hydrosilylation of Hydroxy Amides
Figure 1. Selected examples of pharmaceuticals containing β- or γhydroxy amine motifs.
amides constitutes an important transformation for amine synthesis. Traditional methods using aluminum hydrides and borohydrides, however, often exhibit poor tolerance toward other more reducible functional groups.2 In an effort to improve the chemoselectivity, catalytic hydrosilylation of amides has been intensively investigated.3 Various metalbased catalytic systems, such as Ru,4 Pt,5 Rh,6 Ir,7 Fe,8 Zn,9 Cu,10 Au,11 Co,12 Mg,13 and In,14 are effective for this purpose. Alternatively, a few organocatalysts, such as tris(pentafluorophenyl)borane (B(C6F5)3),15 boronic acids,16 and triphenylborane (BPh3),17 have emerged for “metal-free” protocols that allow for novel reactivity and chemoselectivity. Most of these catalysts, however, are only suitable for the reduction of tertiary amides, which are more reactive than secondary amides. Furthermore, very few methods are available in terms of site-selective reduction of a specific amide group among many others when the substrates contain multiple amide groups.18 Hence, the development of a method for amide reduction, especially secondary amides, at a specific site with broad functional group tolerance is highly desirable. © XXXX American Chemical Society
For the synthesis of hydroxy amines from hydroxy amides through catalytic chemo- and regioselective hydrosilylation, we were particularly interested in use of organocatalyst B(C6F5)3, which exhibits unique reactivity for both silylation of alcohols19 and hydrosilylation of amides15 (Scheme 1). We envisioned that the hydroxy group of a hydroxy amide substrate could first react with a hydrosilane to form silyl ether A in a dehydrogenative manner.19 Another hydride atom of the Received: September 20, 2018
A
DOI: 10.1021/acs.orglett.8b03014 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
temperature (entries 8 and 9). Therefore, at least two hydride atoms on a silicon atom are necessary for the amide reduction to proceed. Among the solvents examined, 1,4-dioxane and toluene produced the best results (entries 3 and 10). The observed reactivity and selectivity in the two-substrate system shown in Table 1 supported the reaction design shown in Scheme 1. In sharp contrast to entry 10, hydrosilylation of 1a did not proceed at all when B(C6F5)3 was replaced by other boron catalysts, such as Ph3B,17 and boronic acids 3,16b 4,16b and 5.16a We next investigated the substrate scope of hydroxy amides under the optimized conditions (Scheme 2). In previously
hydrosilane could be abstracted by B(C6F5)3 to form ion pair B comprising a cationic silicon atom and a hydroborate anion. The amide carbonyl group of this ion-pair intermediate would be activated by coordination to the Lewis acidic silicon atom,20 allowing for subsequent reduction by the hydroborate to give the O-silyl hemiaminal species C.15b Further reaction of C with hydrosilane and B(C6F5)3 would then lead to silyl ether E.21 Finally, the hydroxy amine product could be released after desilylation. To test our hypothesis, we initially investigated the directing effect of a hydroxy group in the B(C6F5)3-catalyzed hydrosilylation of a mixture of amides 1a and 1a′ in the presence of different hydrosilanes (Table 1). With trihydride silane
Scheme 2. Scope of Hydroxy-Directed Reduction of Amidesa
Table 1. Structural Effect of Hydrosilanes for Selective Reduction of Hydroxy Amidea
a
The reactions were carried out with 1a (0.1 mmol), 1a′ (0.1 mmol), B(C6F5)3 (0.01 mmol), and hydrosilane (hydride atoms = 4.0 equiv) in 1,4-dioxane (1.0 mL) at 40 °C for 24 h. bNMR yield. cPhMe was used as the solvent instead of 1,4-dioxane. a
All reactions were run on a 0.2 mmol scale of amides. Isolated yields are given. Yields based on converted starting material are indicated in parentheses.
PhSiH3, β-hydroxy amide 1a was selectively reduced, affording 2a in moderate yield (33%, entry 1). Amine product 2a′, derived from simple amide 1a′, was produced in only trace amounts. Screening dihydride silanes (entries 2−7) revealed that the selective hydrosilylation proceeded best with PhMeSiH2, affording 2a in nearly quantitative yield (96%, entry 3). Poor selectivity was realized with tetramethyldisiloxane and octamethyltetrasiloxane (entries 6 and 7), suggesting that the selectivity of the reduction might be sensitive to the distance between the two Si−H groups. Monohydride silanes were only reactive for the first silylation step of the hydroxy group, leaving the amide bonds intact under a mild
reported B(C6F5)3-catalyzed hydrosilylations, the reduction of tertiary amides proceeded at elevated temperatures (50−130 °C), while N-alkyl-substituted secondary amides were unreactive.15 In the present case, however, the secondary amines were obtained from α- or β-hydroxy amides in high yields under mild conditions (rt to 60 °C) (2a−n). It is noteworthy that the highly challenging secondary amide in 1o derived from phenylalanine was selectively reduced with good B
DOI: 10.1021/acs.orglett.8b03014 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Figure 2. (a) Site-selective hydrosilylation of cyclosporin A. 2v was isolated in 25% yield (89% yield based on converted 1v). (b) HPLC chromatogram of the reaction mixture. After quenching with TBAF, the less polar silanes in the mixture were washed out through silica gel flash column chromatography. The remaining organic components were combined for HPLC analysis (detected at 214 nm).
bond worked as the directing group for the silanes. This method was applicable to the reduction of N-alkyl-substituted secondary amides, which were difficult to reduce using the previously available methods, with high functional group tolerance. The present reaction was successfully applied to chemo- and site-selective reduction of a specific amide bond of cyclosporin A possessing 11 amide bonds. This catalytic method will be applicable for complex molecule synthesis and drug discovery.
yield (42%). The phenolic hydroxy group also worked as the directing site for the hydrosilane, which allowed for hydrosilylation under mild conditions (50−60 °C, 2q−u). In diamide substrates 1p (tertiary amide) and 1u (secondary amide), the amides proximal to hydroxy groups were siteselectively reduced in good yields.22 Functional groups that are sensitive to reduction conditions, such as ester (1o and 1r), nitro (1s), and halo (1g−i, and 1t) groups, were tolerated. Moreover, we synthesized 0.6 g of 2a from 1a (53%), which illustrated the potential utility of this method in a large-scale synthesis (see the Supporting Information). Finally, to demonstrate adaptability to complex substrates, we applied the current hydrosilylation conditions to the siteselective reduction of a pharmaceutically important cyclic peptide, cyclosporin A (1v), which comprises 11 amino acids with four secondary and seven tertiary amide bonds. Cyclosporin A was gradually consumed in the presence of B(C6F5)3 (20 mol %) and PhMeSiH2 (2.0 equiv) at 50 °C, providing the reduced form 2v in 25% isolated yield after 48 h, with 72% 1v recovered (Figure 2a). HPLC analysis of the crude mixture revealed that the reaction was rather clean (Figure 2b). The HRMS spectrum of the isolated product 2v showed signals at m/z = 1188.8699 for [M + H]+ (calcd m/z = 1188.8694) and 1210.8514 for [M + Na]+ (calcd m/z = 1210.8513). The structure of 2v was further confirmed by 1H and 13C NMR spectroscopy. Four proton signals were observed for the amide NH groups in cyclosporin A, while only three signals were found for 2v, indicating the reduction of only one amide group. Furthermore, signals for the newly formed CH2 group were observed in both the 1H (2.42−2.18 ppm) and 13C NMR (46.28 ppm) spectra of 2v. The position of this CH2 group was also confirmed by the 1H−1H COSY and 1H−13C HMQC correlations. The signals for the CC bond remained intact in 13C NMR (129.90 and 125.99 ppm), indicating that the alkene functionality was not affected. Unlike the reported reduction using a Rh complex, in which the most reactive tertiary amide site was selectively reduced,6 the chemo- and site-selectivity of the B(C6F5)3−PhMeSiH2 system developed here relied on the adjacent hydroxy group. This result clearly demonstrates that the present method is reliable even when using a complex peptide substrate. In summary, for the B(C6F5)3-catalyzed dehydrogenative silylation of a hydroxy group by a dihydrosilane and intramolecular Lewis acid−base interaction between the silicon atom and the amide carbonyl oxygen atom, we developed the first chemo- and site-selective hydrosilylation of an amide bond of hydroxy amides. The hydroxy group proximal to the amide
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03014. General experimental procedures and characterization of the products (PDF)
■
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected] ORCID
Motomu Kanai: 0000-0003-1977-7648 Author Contributions †
J.N. and T.O. contributed equally.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This work was supported in part by JSPS KAKENHI Grant Nos. JP17H06442 (M.K.) (Hybrid Catalysis), 17H01522 (M.K.), 17K19479 (M.K.), and 16H06216 (Y.S.).
■
REFERENCES
(1) McGrath, N. A.; Brichacek, M.; Njardarson, J. T. J. Chem. Educ. 2010, 87, 1348. (2) (a) Seyden-Penne, J. Reductions by the Alumino- and Borohydrides in Organic Synthesis, 2nd ed.; Wiley: New York, 1997. (b) Gribble, W. G. Chem. Soc. Rev. 1998, 27, 395. (3) For recent reviews, see: (a) Volkov, A.; Tinnis, F.; Slagbrand, T.; Trillo, P.; Adolfsson, H. Chem. Soc. Rev. 2016, 45, 6685−6697. (b) Chardon, A.; Morisset, E.; Rouden, J.; Blanchet, J. Synthesis 2018, 50, 984−997. (4) (a) Hanada, S.; Ishida, T.; Motoyama, Y.; Nagashima, H. J. J. Org. Chem. 2007, 72, 7551−7559. (b) Reeves, J. T.; Tan, Z.; Marsini,
C
DOI: 10.1021/acs.orglett.8b03014 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters M. A.; Han, Z. S.; Xu, Y.; Reeves, D. C.; Lee, H.; Lu, B. Z.; Senanayake, C. H. Adv. Synth. Catal. 2013, 355, 47−52. (5) Hanada, S.; Tsutsumi, E.; Motoyama, Y.; Nagashima, H. J. Am. Chem. Soc. 2009, 131, 15032−15040. (6) Das, S.; Li, Y.; Bornschein, C.; Pisiewicz, S.; Kiersch, K.; Michalik, D.; Beller, M. Angew. Chem., Int. Ed. 2015, 54, 12389− 12393. (7) Cheng, C.; Brookhart, M. J. J. Am. Chem. Soc. 2012, 134, 11304− 11307. (8) (a) Sunada, Y.; Kawakami, H.; Imaoka, T.; Motoyama, Y.; Nagashima, H. Angew. Chem., Int. Ed. 2009, 48, 9511−9514. (b) Das, S.; Wendt, B.; Möller, K.; Junge, K.; Beller, M. Angew. Chem., Int. Ed. 2012, 51, 1662−1666. (c) Tsutsumi, H.; Sunada, Y.; Nagashima, H. Chem. Commun. 2011, 47, 6581−6583. (d) Volkov, A.; Buitrago, E.; Adolfsson, H. Eur. J. Org. Chem. 2013, 2013, 2066−2070. (e) Zhou, S.; Junge, K.; Addis, D.; Das, S.; Beller, M. Angew. Chem., Int. Ed. 2009, 48, 9507−9510. (f) Blom, B.; Tan, G.; Enthaler, S.; Inoue, S.; Epping, J. D.; Driess, M. J. Am. Chem. Soc. 2013, 135, 18108−18120. (9) Das, S.; Addis, D.; Zhou, S.; Junge, K.; Beller, M. J. Am. Chem. Soc. 2010, 132, 1770−1771. (10) Das, S.; Join, B.; Junge, K.; Beller, M. Chem. Commun. 2012, 48, 2683−2685. (11) Mikami, Y.; Noujima, A.; Mitsudome, T.; Mizugaki, T.; Jitsukawa, K.; Kaneda, K. Chem. - Eur. J. 2011, 17, 1768−1772. (12) Dombray, T.; Helleu, C.; Darcel, C.; Sortais, J.-B. Adv. Synth. Catal. 2013, 355, 3358−3362. (13) Lampland, N. L.; Hovey, M.; Mukherjee, D.; Sadow, A. D. ACS Catal. 2015, 5, 4219−4226. (14) Sakai, N.; Takeoka, M.; Kumaki, T.; Asano, H.; Konakahara, T.; Ogiwara, Y. Tetrahedron Lett. 2015, 56, 6448−6451. (15) (a) Tan, M.; Zhang, Y. Tetrahedron Lett. 2009, 50, 4912−4915. (b) Blondiaux, E.; Cantat, T. Chem. Commun. 2014, 50, 9349−9352. (c) Chadwick, R. C.; Kardelis, V.; Lim, P.; Adronov, A. J. Org. Chem. 2014, 79, 7728−7733. (16) (a) Li, Y.; de La Torre, J. A. M.; Grabow, K.; Bentrup, U.; Junge, K.; Zhou, S.; Brgckner, A.; Beller, M. Angew. Chem., Int. Ed. 2013, 52, 11577−11580. (b) Chardon, A.; Mohy El Dine, T.; Legay, R.; De Paolis, M.; Rouden, J.; Blanchet, J. Chem. - Eur. J. 2017, 23, 2005−2009. (17) Mukherjee, D.; Shirase, S.; Mashima, K.; Okuda, J. Angew. Chem., Int. Ed. 2016, 55, 13326−13329. (18) For one very rare example showing that tertiary amides could be selectively reduced in the presence of secondary amides and other functional groups, see ref 6. (19) Blackwell, J. M.; Foster, K. L.; Beck, V. H.; Piers, W. E. J. J. Org. Chem. 1999, 64, 4887−4892. (20) For a hydroxy group directed, metal-catalyzed amidation, see: Tsuji, H.; Yamamoto, H. J. Am. Chem. Soc. 2016, 138, 14218−14221. (21) From intermediate D to E, imine (in the case of a secondary amide) or iminium (in the case of a tertiary amide) species might be formed. See refs 15a and 17. (22) The side products derived from reduction at the undesired site were detected in very small amounts based on LC−MS analysis.
D
DOI: 10.1021/acs.orglett.8b03014 Org. Lett. XXXX, XXX, XXX−XXX
