Letter pubs.acs.org/OrgLett
Highly Enantioselective Arylation of N,N‑DimethylsulfamoylProtected Aldimines Using Simple Sulfur−Olefin Ligands: Access to Solifenacin and (S)‑(+)-Cryptostyline II Tao Jiang,†,‡ Wen-Wen Chen,† and Ming-Hua Xu*,† †
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China ‡ University of Chinese Academy of Sciences, Beijing 100049, China S Supporting Information *
ABSTRACT: With the use of a simple sulfur−olefin ligand, a highly enantioselective rhodium-catalyzed addition of arylboroxines to N,N-dimethylsulfamoyl-protected aldimines has been achieved, allowing access to a broad range of chiral diarylmethylamines in high yields (up to 98%) with uniformly excellent enantioselectivities (up to 99% ee). This catalyst system is also applicable to the arylation of N-tosyl arylimines. By utilizing this method, some biologically active molecules possessing a chiral 1-aryl-1,2,3,4-tetrahydroisoquinoline core such as Solifenacin and (S)-(+)-Cryptostyline II are facilely constructed.
O
Scheme 1. Rh-Catalyzed Asymmetric Arylation of N,NDimethylsulfamoyl Imines
ptically active diarylmethylamines are embodied in a variety of biologically significant compounds.1 Due to their pharmaceutical importance, great attention has been drawn to the development of their synthesis.2 Since the first report by Tomioka in 2004,3a rhodium-catalyzed asymmetric addition of arylboron reagents to aldimines has been recognized as a particularly attractive and powerful strategy for efficient enantioselective assembly of the skeleton.3 Although some major achievements have been made; however, most methods rely on the use of N-tosyl or nosyl activated/protected imines, which suffers from the disadvantage of protecting group removal under relatively harsh or environmentally unfriendly conditions. To address this issue, N,N-dimethylsulfamoyl was developed as an inexpensive, low-molecular-weight, and easily removable protecting group for this transformation. In 2006, de Vries, Feringa, and Minnaard4 reported the first development of a monodentate, para-methoxyaniline-derived phosphoramidite as the chiral ligand for Rh-catalyzed asymmetric arylation of N,Ndimethylsulfamoyl imines. Later, Du5 applied binaphthyl-based chiral diene ligands in the same reaction, providing the diarylmethylamine products with up to 84% ee (Scheme 1). Despite this remarkable progress, the substrate generality is likely influenced by the electronic and steric substitution pattern of both reaction partners and the enantioselectivities require further improvement. Quite recently, Kim6 disclosed the use of a chiral bicyclic bridgehead phosphoramidite ligand and found that the reactions with phenyl, p-methoxyphenyl, p-tolyl, and m-tolyl boronic acids could occur with high stereocontrol (87−96% ee). However, the yield dropped dramatically with m-tolyl boronic © 2017 American Chemical Society
acid and no product was attained with more sterically hindered otolyl boronic acid. To date, there are no other known reports of enantioselective arylation of N,N-dimethylsulfamoyl imines, presumably due to the diminished reactivity of these substrates relative to N-tosyl and nosyl imines as well as the difficulty in controlling the diaryl stereodifferentiation. Therefore, the development of a new, benign, and effective catalyst system that Received: March 15, 2017 Published: April 7, 2017 2138
DOI: 10.1021/acs.orglett.7b00776 Org. Lett. 2017, 19, 2138−2141
Letter
Organic Letters
and stereochemical control (L5, 86% yield, 95% ee) (entry 5). Similar enantioselectivity was obtained with the use of weak base K2CO3 (entry 6). In addition, varying the solvent did not furnish better results (entries 7 and 8). Notably, only a trace amount of product was detected in water-miscible solvent dioxane due to the drastic hydrolysis of substrate under the basic conditions (entry 7). In contrast to SOLs, C2-symmetric chiral diene ligands L6 and L7 exhibited much lower reactivity (19−20% yields) in spite of comparable enantiocontrol performance (entries 9 and 10), while bisphosphine ligand BINAP could hardly catalyze the reaction (entry 11). Having established the optimal ligand and reaction parameters, we then investigated the substrate scope of this Rh-catalyzed asymmetric arylation (Scheme 2). We were pleased to find that a
would successfully lead to a broad range of desired diarylmethylamines with great enantioselectivities still represents a challenging task and is highly desirable. In the past few years, chiral sulfur-based olefins have emerged as a new promising class of hybrid ligands for asymmetric catalysis.7 Our group has demonstrated that simple and readily available chiral sulfinamide-olefins could display great catalytic activities and enantioselectivities in a series of Rh-catalyzed asymmetric additions to carbonyl compounds and cyclic N-sulfonyl imines.8 Encouraged by these results, we sought to further explore this chemistry in the enantioselective arylation of acyclic imines. Herein, we describe our development of an elegant catalyst system for the highly enantioselective arylation of N,Ndimethylsulfamoyl aryl imines, enabling access to chiral diarylmethylamines with excellent ee in high yields (Scheme 1). Using our previously developed sulfur−olefin ligands (SOLs) L1−L3 as chiral ligands, we initially performed the reaction between N,N-dimethylsulfamoyl imine 1a and p-methylphenylboroxine 2a in the presence of 1.5 mol % of [Rh(COE)2Cl]2 under aqueous KOH (1.5 M)/toluene at 60 °C (Table 1, entries
Scheme 2. Rh-Catalyzed Asymmetric Arylation of N,NDimethylsulfamoyl Iminesa−d
Table 1. Ligand Screening and Optimization of Reaction Conditionsa
entry
ligand
base(aq)
solvent
yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9 10 11
L1 L2 L3 L4 L5 L5 L5 L5 L6 L7 L8
KOH KOH KOH KOH KOH K2CO3 KOH KOH KOH KOH KOH
toluene toluene toluene toluene toluene toluene dioxane DCE toluene toluene toluene
60 83 79 66 86 80 trace 75 20 19 trace
−81 81 80 84 95 94 − 93 96 91 −
a Conditions: 1a (0.20 mmol), 2a (boroxine, 1.0 equiv), [Rh(COE)2Cl]2 (1.5 mol %), ligand (3.3 mol %), and base (1.5 M, 3.0 equiv) in 1.0 mL of solvent at 60 °C for 6 h. bIsolated yield. c Determined by chiral HPLC analysis.
a Conditions: 1 (0.20 mmol), 2 (1.0 equiv), [Rh(COE)2Cl]2 (1.5 mol %), L5 (3.3 mol %), and KOH (1.5 M, 3.0 equiv) in 1.0 mL of toluene at 60 °C for 6 h. bIsolated yield. cDetermined by chiral HPLC. dThe absolute stereochemistry was determined by comparing the [α]D with known data.4 eReaction at a 1 mmol scale.
1−3). As expected, these Rh(I)/SOLs were found to be able to catalyze the reaction smoothly. Compared with the linear ligand L1, the branched SOL L2 and L3 exhibited higher catalytic activity while maintaining the same level of enantioselectivity (80−81% ee) (entries 1−3). These results inspired us to evaluate other branched SOLs with different substituents. Changing the phenyl group in L3 to the bulkier 1-naphthyl group resulted in a slight increase in enantiocontrol (L4, 84% ee, entry 4). Gratifyingly, the incorporation of a sterically hindered t-Bu group was found to be clearly beneficial for both catalyst activity
variety of arylboroxines bearing substituents with diverse electronic and steric properties all smoothly reacted with N,Ndimethylsulfamoyl imine 1a to provide the desired products in good yields with excellent enantioselectivities (90−99% ee) (3a− i). Extremely high enantiomeric excesses (98−99% ee) were attained with electron-deficient or sterically encumbered arylboroxines (3c−f and 3h). Furthermore, a broad range of electronically and sterically different aryl imines was tested. 2139
DOI: 10.1021/acs.orglett.7b00776 Org. Lett. 2017, 19, 2138−2141
Letter
Organic Letters Regardless of the substitution pattern on the phenyl ring, all these imines reacted well with arylboroxines to provide the corresponding diarylmethylamines in good yields with excellent levels of enantioselectivity (90−99% ee) (3j−m, 3o, 3a′−c′, and 3h′). Interestingly, significant enantiocontrol was observed with electron-rich imines; this trend is opposite to what is observed with arylboroxines. Thus, in some cases such as for 3a′ and 3b′, by simply reversing the corresponding Ar1 and Ar2 groups of the two substrates, the ee of the product can be readily enhanced (3a vs 3a′, 3b vs 3b′, and also 3c′ vs 3c). These results indicate that even minor disadvantages of using electron-deficient imines or electron-rich arylboroxines could be overcome to furnish the desired highly enantioenriched product by easily switching the aryl acceptor/donor and changing the ligand configuration. Moreover, the heteroaromatic imine substrate containing a furan ring also proved competent in the arylation, affording 3n with excellent ee (98%), albeit in a decreased yield (52%). Another fascinating feature is that the reaction exhibits a truly remarkable ortho-substitution tolerance. In all cases with sterically encumbered substrates, as exemplified by 3f, 3h, 3m, 3n, and 3h′, nearly perfect enantiomeric excesses (97−99% ee) could be achieved. Under the optimal reaction conditions, we further explored the scope of N,N-dimethylsulfamoyl imine substrates using aldimine 4 containing an ortho-ester functionality as a more challenging reactant. To our delight, the expected chiral 3-substituted phthalimidine product 5 was afforded through the diarylmethylamine formation followed by in situ lactamization in good yield (84%) with satisfactory enantioselectivity (97% ee) when the reaction was performed under the same catalysis at slightly higher temperature (Scheme 3).
Scheme 5. Rhodium-Catalyzed Asymmetric Arylation of NTosylphenylimine with Arylboroxines
On the basis of the stereochemical outcome of the reaction, a plausible enantio-determining transition-state model is proposed. As shown in Figure 1, the arylrhodium species has a favored
Figure 1. Proposed transition state models for enantioselectivity.
conformation with the aryl group positioned trans to the olefin moiety of ligand and the tert-butyl group is staggered. To avoid the steric congestion, the imine substrate coordinates to rhodium preferentially from its si face, in which the N,N-dimethylsulfamoyl (or tosyl) group orients away from the bulky R substituent on the double bond of the ligand, and consequently the carborhodation takes place to afford the observed major enantiomer. To demonstrate the practical synthetic utility of this method, we carried out the asymmetric synthesis of two biologically important molecules. Solifenacin10,11 is a urinary antispasmodic prescription drug used for the treatment of an overactive bladder. Chiral resolution,11 asymmetric hydrogenation,12 and deracemization13 of 1-phenyl-1,2,3,4-tetrahydroisoquinoline are the main strategies to access its chiral tetrahydroisoquinoline core. By taking advantage of the extraordinary ortho-substitution compatibility of our protocol, asymmetric synthesis of enatiomerically pure diarylmethylamine 3p (99% ee) was accomplished with ease in 82% yield. Removal of the N,N-dimethylsulfamoyl group followed by ethoxycarbonylation and TBS-deprotection furnished the intermediate 9. Subsequently, the intramolecular Mitsunobu reaction of 9 with DIAD/PPh3 gave (S)-1-phenyl1,2,3,4-tetrahydroisoquinoline derivative 10, which could be easily transformed into (+)-Solifenacin by means of transesterification with (R)-3-quinuclidinol following the known procedure11 (Scheme 6a). In a similar fashion, arylation product 3q was accessed in high yield (96%) as a single enantiomer (99% ee) using the same catalyst system. N-Deprotection of 3q under microwave irradiation, followed by reprotection with Boc, yielded the intermediate 11 with complete preservation of the optical purity. Treatment of N-Boc amine 11 with LAH in refluxing THF gave the corresponding N-methyl amino alcohol, which was smoothly cyclized under Mitsunobu conditions to give (S)(+)-Cryptostyline II in 88% yield over two steps. The total yield of this method is 79%, which compares very favorably with the previous synthesis14 (19%,14a 27%,14b and 37%14c). Notably, (S)Cryptostylines I (R1 = H; R2, R3 = O−CH2−O), II (R1 = H; R2, R3 = OCH3), and III (R1, R2, R3 = OCH3) are natural products isolated from the plant Cryptostylis f ulva15a,b and reported as probes for dopamine receptor D115c (Scheme 6b). With the same strategy, it is believed that (S)-(+)-Cryptostylines I and III could also be readily prepared with appropriate arylboroxines. In summary, a rather simple but highly effective rhodium/ sulfur−olefin catalyst system for asymmetric addition of
Scheme 3. Synthesis of Chiral 3-Substituted Phthalimidine 5
Subsequently, the removal of the N,N-dimethylsulfamoyl group was conducted.4 As exemplified by 3c, cleavage of the N−S bond proceeded readily within 30 min in 1,3-diaminopropane under microwave-assisted heating conditions, giving the Nfree diarylmethylamine 6 in almost quantitative yield without loss of optical purity9 (Scheme 4). Scheme 4. Removal of the N,N-Dimethylsulfamoyl Group
To further extend the substrate generality of this catalyst system, we examined the reaction of N-tosylarylimines with arylboroxines. As shown in Scheme 5, a similar trend as that for the arylation of N,N-dimethylsulfamoyl arylimines was observed, with uniformly high enantioselectivities (91−99% ee) being achieved in the Rh/L5-catalyzed asymmetric arylation of Ntosylphenylimine 7; the reaction also works optimally with electron-deficient or sterically encumbered arylboroxines (8b and 8d, 98−99% ee). 2140
DOI: 10.1021/acs.orglett.7b00776 Org. Lett. 2017, 19, 2138−2141
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Organic Letters
Municipal Committee of Science and Technology (14xd1404400) is greatly acknowledged.
Scheme 6. Facile Asymmetric Synthesis of Solifenacin and (S)(+)-Cryptostyline II
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(1) (a) Spencer, C. M.; Faulds, D.; Peters, D. H. Drugs 1993, 46, 1055. (b) Nugent, T. C. Chiral Amine Synthesis: Methods, Developments and Applications; Wiley-VCH: Weinheim, Germany, 2010. (2) For reviews on catalytic enantioselective addition to imines, see: (a) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069. (b) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011, 111, 2626. For a review on synthesis of chiral diarylmethylamines, see: (c) Schmidt, F.; Stemmler, R. T.; Rudolph, J.; Bolm, C. Chem. Soc. Rev. 2006, 35, 454. For a review on catalytic asymmetric arylations, see: (d) Bolm, C.; Hildebrand, J. P.; Muñiz, K.; Hermanns, N. Angew. Chem., Int. Ed. 2001, 40, 3284. (3) For representative examples on catalytic rhodium-catalyzed arylations of imines with arylboron reagents, see: (a) Kuriyama, M.; Soeta, T.; Hao, X.; Chen, Q.; Tomioka, K. J. Am. Chem. Soc. 2004, 126, 8128. (b) Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2004, 126, 13584. (c) Weix, D. J.; Shi, Y. L.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 1092. (d) Otomaru, Y.; Tokunaga, N.; Shintani, R.; Hayashi, T. Org. Lett. 2005, 7, 307. (e) Duan, H. F.; Jia, Y. X.; Wang, L. X.; Zhou, Q. L. Org. Lett. 2006, 8, 2567. (f) Nakagawa, H.; Rech, J. C.; Sindelar, R. W.; Ellman, J. A. Org. Lett. 2007, 9, 5155. (g) Wang, Z.-Q.; Feng, C.-G.; Xu, M.-H.; Lin, G.-Q. J. Am. Chem. Soc. 2007, 129, 5336. (h) Trincado, M.; Ellman, J. A. Angew. Chem., Int. Ed. 2008, 47, 5623. (i) Cui, Z.; Yu, H.-J.; Yang, R.-F.; Gao, W.Y.; Feng, C.-G.; Lin, G.-Q. J. Am. Chem. Soc. 2011, 133, 12394. (j) Chen, C.-C.; Gopula, B.; Syu, J.-F.; Pan, J.-H.; Kuo, T.-S.; Wu, P.-Y.; Henschke, J. P.; Wu, H.-L. J. Org. Chem. 2014, 79, 8077. (4) Jagt, R. B. C.; Toullec, P. Y.; Geerdink, D.; de Vries, J. G.; Feringa, B. L.; Minnaard, A. J. Angew. Chem., Int. Ed. 2006, 45, 2789. (5) Cao, Z.; Du, H. Org. Lett. 2010, 12, 2602. (6) Lee, A.; Kim, H. J. Org. Chem. 2016, 81, 3520. (7) For reviews, see: (a) Feng, X.; Du, H. Asian J. Org. Chem. 2012, 1, 204. (b) Li, Y.; Xu, M.-H. Chem. Commun. 2014, 50, 3771. (8) (a) Wang, H.; Jiang, T.; Xu, M.-H. J. Am. Chem. Soc. 2013, 135, 971. (b) Wang, H.; Xu, M.-H. Synthesis 2013, 45, 2125. (c) Wang, H.; Li, Y.; Xu, M.-H. Org. Lett. 2014, 16, 3962. (d) Jiang, T.; Xu, M.-H. Org. Lett. 2015, 17, 528. (e) Li, Y.; Yu, Y.-N.; Xu, M.-H. ACS Catal. 2016, 6, 661. (f) Zhang, Y.-F.; Chen, D.; Chen, W.-W.; Xu, M.-H. Org. Lett. 2016, 18, 2726. (g) Zhang, X.; Xu, B.; Xu, M.-H. Org. Chem. Front. 2016, 3, 944. (9) Determined by chiral HPLC analysis of its N-Boc derivative. (10) Kothari, H. M.; Dave, M. G.; Pandey, B. PCT Int. Appl. WO 2011/ 048607. (11) Naito, R.; Yonetoku, Y.; Okamoto, Y.; Toyoshima, A.; Ikeda, K.; Takeuchi, M. J. Med. Chem. 2005, 48, 6597. (12) (a) Chang, M.; Li, W.; Zhang, X. Angew. Chem., Int. Ed. 2011, 50, 10679. (b) Ye, Z.-S.; Guo, R.-N.; Cai, X.-F.; Chen, M.-W.; Shi, L.; Zhou, Y.-G. Angew. Chem., Int. Ed. 2013, 52, 3685. (c) Ružič, M.; Pečavar, A.; Prudič, D.; Kralj, D.; Scriban, C.; Zanotti-Gerosa, A. Org. Process Res. Dev. 2012, 16, 1293. (13) (a) Ghislieri, D.; Green, A. P.; Pontini, M.; Willies, S. C.; Rowles, I.; Frank, A.; Grogan, G.; Turner, N. J. J. Am. Chem. Soc. 2013, 135, 10863. (b) Ji, Y.; Shi, L.; Chen, M.-W.; Feng, G.-S.; Zhou, Y.-G. J. Am. Chem. Soc. 2015, 137, 10496. (14) For representative examples of asymmetric synthesis, see: (a) Munchhof, M. J.; Meyers, A. I. J. Org. Chem. 1995, 60, 7086. (b) Umetsu, K.; Asao. Tetrahedron Lett. 2008, 49, 2722. (c) Kurihara, K.; Yamamoto, Y.; Miyaura, N. Adv. Synth. Catal. 2009, 351, 260. (d) Yamato, M.; Hashigaki, K.; Qais, N.; Ishikawa, S. Tetrahedron 1990, 46, 5909. (15) (a) Leander, K.; Luning, B.; Ruusa, E. Acta Chem. Scand. 1969, 23, 244. (b) Brossi, A.; Teitel, S. Helv. Chim. Acta 1971, 54, 1564. (c) Minor, D. L.; Wyrick, S. D.; Charifson, P. S.; Watts, V. J.; Nichols, D. E.; Mailman, R. B. J. Med. Chem. 1994, 37, 4317.
arylboron reagents to acyclic N,N-dimethylsulfamoyl as well as tosyl imines has been successfully developed. The method exhibits unprecedentedly broad substrate generality, particularly enabling access to a wide range of diarylmethylamines having a readily removable N-protecting group in good to excellent yields (up to 98%) with uniformly high enantioselectivities (up to 99% ee). Of particular note, our catalyst system overcomes not only the limitations previously associated with the substrate electronic nature and substitution pattern but also the difficulties in achieving excellent diaryl stereofacial differentiation. The synthetic utility of this protocol is highlighted by the facile and expedient construction of stereodefined 1-aryl-1,2,3,4tetrahydroisoquinolines, which are important structural motifs found in many biologically active compounds, providing a new practical synthetic route to drug molecule Solifenacin and natural alkaloid (S)-(+)-Cryptostyline II.
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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.7b00776. Experimental procedures, characterization data, and copies of NMR and HPLC spectra (PDF)
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REFERENCES
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Ming-Hua Xu: 0000-0002-1692-2718 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support from the National Natural Science Foundation of China (21325209, 21472205, 81521005) and the Shanghai 2141
DOI: 10.1021/acs.orglett.7b00776 Org. Lett. 2017, 19, 2138−2141
