Letter pubs.acs.org/OrgLett
Role of Configuration at C6 in Catalytic Activity of L‑Proline-Derived Bifunctional Organocatalysts Hui Jin, Soo Min Cho, Juyeol Lee, and Do Hyun Ryu* Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Korea S Supporting Information *
ABSTRACT: L-Proline-derived chiral bifunctional (thio)urea organocatalysts epiPTU and epi-PU were newly synthesized, and their catalytic performances were compared with their C6 epimeric catalysts PTU and PU in various Michael reactions of nitrostyrene in terms of reactivities and stereoselectivities. The experimental results indicate that a proper relative stereochemistry at C2 and C6 in L-proline-derived bifunctional organocatalysts is important for successful catalysis and that catalysts (PTU and PU) with the 2S,6R configuration are much more efficient. Without a doubt, amino acid proline occupied a “privileged” status in the development of enantioselective catalysis. Developing efficient chiral ligands or organocatalysts based on the proline scaffold has attracted much attention.7 Recently, we reported a series of novel L-proline-derived tertiary amine bifunctional organocatalysts, which were applied to asymmetric Michael additions to nitroolefins using dithiomalonates8a and 2oxochroman-3-carboxylate esters8b as nucleophiles. In both of our cases, our thiourea catalyst PTU (Figure 2) showed better
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s one of the most important classes of noncovalent organocatalysts,1 tertiary amine−(thio)urea organocatalysts have proven quite successful in accomplishing various asymmetric organic transformations. The first tertiary amine− thiourea bifunctional organocatalyst using (1R,2R)-diaminocyclohexane as a chiral scaffold was reported by Takemoto in 2003.2 Subsequently, new kinds of bifunctional organocatalysts based on different chiral scaffolds, such as chiral binaphthyl,3 cinchona alkaloid,4 amino acid,5 and saccharide,6 have been developed and applied to a broad spectrum of reactions. In a 2005 report by Soós, chiral thiourea organocatalysts QTU and epi-QTU (Figure 1) derived from quinine and
Figure 2. L-Proline-derived tertiary amine−(thio)urea catalysts.
efficiency than quinine-derived thiourea QTU. Compared to the performance of the C6 diphenyl-substituted catalyst Ph-PU (Figure 2), PU showed significantly higher catalytic activity and stereoselectivity, which implies an important role of the newly formed C6 stereocenter on the catalytic activity of our catalysts. On the other hand, Kesavan and co-workers reported the C6 epimeric catalyst epi-PTU (Figure 2), which was successfully applied to many asymmetric reactions with good yields and stereoselectivities.9 These results would suggest that both C6 diastereomers of proline-derived thioureas (PTU and epi-PTU) are efficient catalysts, in contrast to the cinchona-derived (thio)urea catalysts (QTU and epi-QTU). These results stimulated our curiosity and compelled us to further investigate the role of the C6 stereocenter on the catalytic activity of these series of catalysts. However, through careful comparison of the reported analytical data of epi-PTU and intermediates with our
Figure 1. Quinine- and epiquinine-derived tertiary amine−thiourea catalysts.
epiquinine, respectively, were applied to the Michael addition between nitromethane and chalcones.4c The catalyst QTU showed good activity and enantioselectivity (71% yield, 95% ee); in contrast, epi-QTU with the “natural” configuration was completely inactive (0% yield). Independently, Connon4d examined the Michael addition of dimethyl malonate to nitroolefins catalyzed by similar catalysts and arrived at the same conclusion that the C8−C9 configuration of the cinchona scaffold is crucial for successful catalysis. C9 epimeric catalysts are remarkably more efficacious than analogues with the “natural” cinchona alkaloid stereochemistry. Since these ground-breaking studies, tremendous progress in other applications has been presented.4 © XXXX American Chemical Society
Received: April 3, 2017
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DOI: 10.1021/acs.orglett.7b01000 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
Scheme 2. Our Route for the Synthesis of Catalysts epi-PTU and epi-PU
and Juaristi’s data,8a,10 we found that Kesavan’s and our catalysts actually possess the same stereochemistry. In this paper, in order to better understand the effects of the relative stereochemistry at C2/C6 on the catalytic activity, the actual C6 epimeric catalysts epi-PTU and epi-PU (see Scheme 2) and the C6 unsubstituted catalyst H-PU (see Scheme 3) were newly synthesized and evaluated as organocatalysts in Michael additions of 2,4-pentanedione, dithiomalonate, and 2-oxochroman-3-carboxylate ester with nitrostyrene. In 2014, Kesavan and co-workers reported the synthesis of epi-PTU starting from phenyl-substituted N-tritylprolinol 1 via the key intermediate azide 2 (Scheme 1, a).9a They reported Scheme 1. Kesavan’s Route for the Synthesis of Catalyst epiPTU
atom due to the inductive effect of the Boc protecting group prevented formation of aziridinium ion intermediate 7. Next, we turned our attention to the key question: the role of the (R)-C6 chiral center of catalyst (S,R)-PTU. To answer this question, we prepared the actual (2S,6S)-epi-PTU and epi-PU catalysts along with C6-unsubstituted H-PU catalyst. In order to synthesize the real C6 epimeric catalysts epi-PTU and epiPU, the Boc protecting group of 5 was changed to trityl, furnishing N-tritylprolinol (S,S)-1 in 40% yield (two steps) (Scheme 2). Next, (S,S)-1 was converted to azide (S,S)-2 (76% yield) under Mitsunobu conditions, with retention of the configuration through the aziridinium ion intermediate epi-4 (Scheme 2). The absolute configuration of (S,S)-2 was confirmed by comparison of NMR (1H and 13C) and optical rotation data of benzyl derivative (S,S)-3 with Juaristi’s data.10 The key intermediate (S,S)-2 was then transformed to 8 by Ndetritylation using 5 N HCl followed by N-methylation. Finally, azide 8 was reduced with LiAlH4 to the amine, which was reacted in situ with 3,5-bis(trifluoromethyl)phenyl isothiocyanate or 3,5-bis(trifluoromethyl)phenyl isocyanate to provide epi-PTU and epi-PU in 82% and 63% yield, respectively. For the synthesis of the C6-unsubstituted catalyst H-PU (Scheme 3), azide 912 was converted to 10 through N-Boc
that they obtained (S,S)-2 through Mitsunobu reaction to give the inverted chiral center. Thereafter, (S,S)-2 was transformed to benzyl derivative 3 and recorded [α]25D −105.0 (c 1.0, CHCl3) for their (S,S)-3.9a However, Juaristi10 and co-workers synthesized both (S,S)-3 and (S,R)-3, of which the stereochemistries were unambiguously confirmed by X-ray analysis and recorded [α]25D +84 (c 1.0, CHCl3) for (S,S)-3 and [α]25D −97 (c 1.0, CHCl3) for (S,R)-3. In our case, we8a also prepared (S,R)-3 and obtained [α]20D −100.4 (c 1.0, CHCl3), which is in accordance with the optical rotation reported by Juaristi and coworkers. Additionally, the NMR spectra10 (1H and 13C) of (S,S)-3 and (S,R)-3 are very different, and the NMR data9a (1H and 13C) of (S,S)-3 reported by the Kesavan group are consistent with those of (S,R)-3. These results indicate that Kesavan’s key intermediate azide is not (S,S)-2 but (S,R)-2. We hypothesize that their Mitsunobu reaction proceeded with retention of configuration,11 actually affording azide (S,R)-2 (Scheme 1, b). The observed retention of configuration of (S,R)-2 in the Mitsunobu reaction is probably due to the involvement of aziridinium ion intermediate 4 (Scheme 1, b). Similar intermediates have previously been proposed by Cossy,11a Juaristi,10 Kałuża,11b and Yamagiwa11c as typical examples of anchimeric assistance of adjacent heteroatom.11 In our synthesis, we applied Cossy’s method for the preparation of phenyl-substituted N-Boc-prolinol 5 (Scheme 2),11a which was further transformed to key intermediate azide 6 under Mitsunobu conditions with inversion of the chiral center. The normal Mitsunobu reaction proceeded well, probably because the reduced nucleophilicity of the nitrogen
Scheme 3. Synthesis of Catalyst H-PU
deprotection and N-methylation. Then azide 10 was transformed to the amine through the Staudinger reaction, followed by addition with 3,5-bis(trifluoromethyl)phenyl isocyanate to afford the desired catalyst H-PU. With several newly synthesized catalysts in hand, their catalytic activities were first examined in the Michael addition of 2,4-pentanedione 11 to nitrostyrene 12 catalyzed by PTU and the newly synthesized epi-PTU. The reactions of 11 (0.5 mmol) and 12 (0.15 mmol) were performed in the presence of 5 mol % catalyst in 1.5 mL of MTBE at rt for 48 h. When PTU B
DOI: 10.1021/acs.orglett.7b01000 Org. Lett. XXXX, XXX, XXX−XXX
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C6 single-phenyl-substituted catalysts (PU and epi-PU) and C6 unsubstituted catalyst H-PU showed similar reactivities, producing adduct 15 in >95% conversion within 60 min. In contrast, bulky C6 diphenyl-substituted catalyst Ph-PU exhibited the lowest reactivity. It is noteworthy that the reaction did not occur without catalyst. In terms of enantioselectivity, catalysts PTU and PU (Table 2, entries 1 and 3) furnished product 15 with high enantioselectivity (81% ee and 90% ee, respectively). In contrast, the C6 epimeric catalysts epi-PTU and epi-PU exhibited different and much lower enantioselectivity, producing adduct 15 in −59% and −72% ee, respectively (Table 2, entries 2 and 4). Catalyst Ph-PU also showed poor enantioselectivity, affording 15 in 49% ee (Table 2, entry 5). Catalyst H-PU, despite its good reactivity, promoted the reaction with the lowest enantioselectivity (Table 2, entry 6). Based on these results, a single phenyl group substitution at the C6 position and the 6R configuration are optimal for L-prolinederived bifunctional organocatalysts. When the catalysts were investigated in the Michael addition of nitrostyrene 12 with the less reactive, unsymmetrical Michael donor 2-oxochroman-3-carboxylate ester 16, the differences in catalyst performance were amplified (Figure 4 and Table 3).
was used as catalyst, the R-form of 13 was produced as the major enantiomer in 95% ee (Table 1, entry 1), which is Table 1. Michael Addition of 2,4-Pentanedione 11 to Nitrostyrene 12 Catalyzed by PTU and epi-PTUa
entry
cat.
yieldb (%)
eec (%)
1 2 3d
PTU epi-PTU epi-PTU
70 88 95
95 −65 96
a The reaction of 11 (0.5 mmol) and 12 (0.15 mmol) was performed in 1.5 mL of MTBE. bIsolated yield. cDetermined by chiral HPLC analysis. dData collected from the literature.9a
consistent with Kesavan’s result (Table 1, entry 3).9a In contrast, when the reaction was catalyzed by epi-PTU, the (S)enantiomer of 13 was obtained as the primary enantiomer in moderate enantioselectivity (65% ee) (Table 1, entry 2). The above results demonstrated that 6R catalyst PTU exhibited superior enantioselectivity compared to the C6 epimeric catalyst epi-PTU, although it had slightly lower activity. For a systematic investigation into the effects of the relative stereochemistry at C2 and C6 of (thio)urea-substituted Lproline-derived organocatalysts, their catalytic activities were examined in the Michael addition of symmetric Michael donor dithiomalonate 14 to nitrostyrene 12 (Figure 3 and Table 2).
Figure 4. Plots of conversion vs time for the Michael addition of 16 to 12 catalyzed by proline-derived urea catalysts. For details, see the Supporting Information.
Table 3. Catalyst Evaluation in the Michael Addition of 2Oxochroman-3-carboxylate Esters 16 to Nitrostyrene 12a Figure 3. Plots of conversion vs time for the Michael addition of 14 to 12 catalyzed by proline-derived urea catalysts. For details, see the Supporting Information.
Table 2. Catalyst Evaluation in the Michael Addition of Dithiomalonate 14 to Nitrostyrene 12a
entry d
1 2 3d 4 5d 6
cat.
yieldb (%)
eec (%)
PTU epi-PTU PU epi-PU Ph-PU H-PU
94 90 96 92 53 93
81 −59 90 −72 49 −13
entry
cat.
time (h)
yieldb (%)
drc
eed (%)
1 2 3 4 5 6
PTU epi-PTU PU epi-PU Ph-PU H-PU
24 72 24 72 72 30
92 82 91 78 32 92
18:1 4:1 10:1 4:1 2:1 3:1
99 −38 99 −63 70 18
a
The reaction of 12 (0.15 mmol) and 16 (0.075 mmol) was performed in 1 mL of MTBE. bIsolated yield. cDetermined by 1H NMR analysis of the crude reaction mixture. dDetermined by chiral HPLC analysis.
Figure 4 shows the conversion vs time graph for the Michael addition of 16 to 12 catalyzed by proline-derived urea catalysts. This graph clearly illustrates the effect of the C6 stereocenter of the catalyst on reactivity. Catalyst PU with the S,R configuration showed remarkably better reactivity, promoting the reaction with up to 98% conversion within 24 h, while catalysts epi-PU, H-PU, and Ph-PU furnished the product with
a
The reaction of 12 (0.15 mmol) and 14 (0.17 mmol) was performed in 1.5 mL of MTBE. bIsolated yield. cDetermined by chiral HPLC analysis. dData collected from the literature.8a
Figure 3 shows plots of conversion vs time for the Michael addition of 14 to 12 catalyzed by proline-derived urea catalysts. C
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(2) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672. (b) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119. (3) (a) Wang, J.; Li, H.; Yu, X.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4293. (b) Peng, F. Z.; Shao, Z. H.; Fan, B. M.; Song, H.; Li, G. P.; Zhang, H. B. J. Org. Chem. 2008, 73, 5202. (c) Lee, H. J.; Kang, S. H.; Kim, D. Y. Synlett 2011, 1559. (4) For reviews, see: (a) Connon, S. J. Chem. Commun. 2008, 2499. (b) Xi, Y.; Shi, X. Chem. Commun. 2013, 49, 8583. For selected examples, see: (c) Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Org. Lett. 2005, 7, 1967. (d) McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367. (e) Li, B. J.; Jiang, L.; Liu, M.; Chen, Y. C.; Ding, L. S.; Wu, Y. Synlett 2005, 603. (f) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481. (g) Wang, Y.; Li, H.; Wang, Y. Q.; Liu, Y.; Foxman, B. M.; Deng, L. J. Am. Chem. Soc. 2007, 129, 6364. (h) Peschiulli, A.; Quigley, C.; Tallon, S.; Gun’ko, Y. K.; Connon, S. J. J. Org. Chem. 2008, 73, 6409. (i) Jang, H. B.; Rho, H. S.; Oh, J. S.; Nam, E. H.; Park, S. E.; Bae, H. Y.; Song, C. E. Org. Biomol. Chem. 2010, 8, 3918. (j) Zhu, N.; Ma, B. C.; Zhang, Y.; Wang, W. Adv. Synth. Catal. 2010, 352, 1291. (k) Arakawa, Y.; Fritz, S. P.; Wennemers, H. J. Org. Chem. 2014, 79, 3937. (l) Cosimi, E.; Saadi, J.; Wennemers, H. Org. Lett. 2016, 18, 6014. (5) Andrés, J. M.; Manzano, R.; Pedrosa, R. Chem. - Eur. J. 2008, 14, 5116. (6) Li, X. J.; Liu, K.; Ma, H.; Nie, J.; Ma, J. A. Synlett 2008, 3242. (7) (a) Zhang, S.; Wang, W. Privileged Chiral Ligands and Catalysts; Zhou, Q.-L., Ed.; Wiley-VCH: Weinheim, 2011; pp 409−445. (b) List, B. Tetrahedron 2002, 58, 5573. (8) (a) Jin, H.; Kim, S. T.; Hwang, G. S.; Ryu, D. H. J. Org. Chem. 2016, 81, 3263. (b) Jin, H.; Cho, S. M.; Hwang, G. S.; Ryu, D. H. Adv. Synth. Catal. 2017, 359, 163. (9) (a) Vinayagam, P.; Vishwanath, M.; Kesavan, V. Tetrahedron: Asymmetry 2014, 25, 568. (b) Pratap Reddy Gajulapalli, V.; Vinayagam, P.; Kesavan, V. Org. Biomol. Chem. 2014, 12, 4186. (c) Reddy Gajulapalli, V. P.; Vinayagam, P.; Kesavan, V. RSC Adv. 2015, 5, 7370. (d) Pratap Reddy Gajulapalli, V.; Lokesh, K.; Vishwanath, M.; Kesavan, V. RSC Adv. 2016, 6, 12180. (e) Vishwanath, M.; Prakash, M.; Vinayagam, P.; Kesavan, V. Synthesis 2016, 48, 2671. (f) Muthusamy, S.; Prakash, M.; Ramakrishnan, C.; Gromiha, M. M.; Kesavan, V. ChemCatChem 2016, 8, 1708. (g) Kumarswamyreddy, N.; Kesavan, V. Org. Lett. 2016, 18, 1354. (h) Vishwanath, M.; Sivamuthuraman, K.; Kesavan, V. Chem. Commun. 2016, 52, 12314. (i) Vishwanath, M.; Vinayagam, P.; Gajulapalli, V.; Kesavan, V. Asian J. Org. Chem. 2016, 5, 613. (10) Vargas-Caporali, J.; Cruz-Hernàndez, C.; Juaristi, E. Heterocycles 2012, 86, 1275. (11) Mitsunobu reactions can proceed with retention of configuration via anchimeric assistance of the adjacent heteroatom in the substrate. For examples, see: (a) Cochi, A.; Burger, B.; Navarro, C.; Pardo, D. G.; Cossy, J.; Zhao, Y.; Cohen, T. Synlett 2009, 2157. (b) Niedziejko, P.; Szewczyk, M.; Kalicki, P.; Kałuża, Z. Tetrahedron: Asymmetry 2015, 26, 1083. (c) Yamagiwa, N.; Watanuki, S.; Nishina, T.; Suto, Y.; Iwasaki, G. Chem. Lett. 2016, 45, 54. (d) Dondoni, A.; Richichi, B.; Marra, A.; Perrone, D. Synlett 2004, 1711. (e) Jeong, L. S.; Yoo, S. J.; Moon, H. R.; Kim, Y. H.; Chun, M. W. J. Chem. Soc., Perkin Trans. 1 1998, 3325. For a review, see: (f) Hughes, D. Org. Prep. Proced. Int. 1996, 28, 127. (12) Dahlin, N.; Bøgevig, A.; Adolfsson, H. Adv. Synth. Catal. 2004, 346, 1101.
77%, 89%, and 23% conversion, respectively, in the same period of time. In addition, the stereoselectivities of the catalysts in the Michael addition of 16 to 12 were determined, and the results are outlined in Table 3. When the reaction was catalyzed by 6Rcatalysts PTU and PU (Table 3, entries 1 and 3), the desired product 17 was obtained with excellent stereoselectivity (18:1 dr, 99% ee and 10:1 dr, 99% ee, respectively). In contrast, the C6 epimeric catalysts epi-PTU and epi-PU exhibited dramatically poorer stereoselectivity, producing adduct 17 in 4:1 dr at −38% ee and 4:1 dr at −63% ee, respectively (Table 3, entries 2 and 4). Consistent with the previous analysis, catalysts Ph-PU and H-PU exhibited deficient stereoselectivity in this case as well (Table 3, entries 5 and 6). The above results demonstrate that the (S,R) configuration of catalysts PTU and PU is crucial for successful catalysis. In summary, comparison of the catalytic activities of (2S,6R)catalysts (PTU and PU), (2S,6S)-catalysts (epi-PTU and epiPU), C6 diphenyl-substituted catalyst Ph-PU, and C6 unsubstituted catalyst H-PU revealed that a proper relative stereochemistry at C2 and C6 in the L-proline-derived bifunctional organocatalyst plays a key role in successful catalyst performance. The (2S,6R)-form catalysts PTU and PU are remarkably more efficacious in terms of stereoselectivity in various Michael reactions of nitrostyrene. Additionally, we revised the original configurational misassignment of epi-PTU catalyst from (2S,6S)-epi-PTU to (2S,6R)-PTU. Studies aimed at investigating the mechanism and developing new organocatalysts based on this efficient chiral scaffold are underway and will be reported in due course.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01000. Experimental procedures and full analytical data (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Do Hyun Ryu: 0000-0001-7615-4661 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This research was supported by National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIP) (Nos. NRF-2016R1A2B3007119 and NRF2016R1A4A1011451).
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REFERENCES
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