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Divergent Synthesis of Chiral Heterocycles via Sequencing of Enantioselective Three-Component Reactions and One-Pot Subsequent Cyclizations Min Tang, Dong Xing,* Haoxi Huang and Wenhao Hu*
Received 00th January 2012, Accepted 00th January 2012 DOI: 10.1039/x0xx00000x www.rsc.org/
A highly efficient sequencing of catalytic asymmetric threecomponent reactions of alcohols, diazo compounds and aldimines/aldehydes with one-pot subsequent cyclizations was reported. The development of a robust and versatile Rh(II)/Zr(IV)-BINOL co-catalytic system not only gives high diastereo- and enantioselective controls of the threecomponent reaction, but also show excellent functionality tolerances that allow a wide range of functionalities to be preinstalled in each component and readily undergo one-pot subsequent cyclizations, thus providing rapid and diversityoriented synthesis (DOS) of different types of chiral nitrogenand/or oxygen-containing polyfunctional heterocycles. Nitrogen- and/or oxygen-containing chiral heterocycles are inarguably among the most abundant structural motifs in biologically active natural products and pharmaceuticals.1 As a result, there has been an increasing demand for chemical libraries of chiral heterocycles in drug discovery process and chemical biological studies. Synthetic strategies for the rapid construction of collections of structurally diverse heterocycles, such as diversity-oriented synthesis (DOS) 2 or multicomponent reactions (MCRs),3 have drawn considerable attention from the synthetic community. Among them, the sequencing of MCRs with subsequent cyclizations, which relies on each component of the MCR to incorporate different functionalities to undergo subsequent cyclizations through functional group pairing, is one of the most promising synthetic strategies for such purpose.2d,2e,3b However, although a number of MCRs have been successfully applied to this sequencing strategy,4 to the best of our knowledge, there are currently no catalytic asymmetric examples of such transformations for the rapid construction of collections of chiral heterocycles. The challenge in realizing this kind of transformations might attribute to the difficulty in discovering a robust catalytic system in enantioselective multi-component
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reactions that can not only provide efficient diastereo- and enantioselective controls, but also show excellent functionality tolerance so different functional groups responsible for subsequent cyclizations could be pre-installed on each component and well tolerated without compromising stereoselectivities (Scheme 1).
Scheme 1 Concept for sequencing enantioselective multi-component reactions with one-pot subsequent cyclizations to generate diverse chiral heterocycles.
As part of our continuous research efforts in developing catalytic asymmetric MCRs through electrophilic trapping of active onium ylides generated from metal carbenes,5-8 we aimed at exploring catalytic systems for such types of MCRs that can not only give efficient stereoselective controls but also show high functionality tolerance for subsequent cyclizations, therefore offering efficient strategies for the rapid construction of versatile chiral heterocycles. We turned our attention to the threecomponent reaction of diazo compounds with alcohols and imines, hoping that the generated chiral β-amino alcohol product would be an ideal structural motif to undergo subsequent cyclization to give various nitrogen- and/or oxygen-containing heterocycles via suitable functional groups pairing strategies. Herein, we report our successful development of a rhodium(II)/Zr(IV)-BINOL co-catalytic system for highly diastereoand enantioselective three-component reaction of diazo
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compounds with alcohols and imines/aldehydes. Taking advantage of the robust co-catalytic system, substrates bearing different pre-installed functionalities readily underwent the sequencing of three-component reactions and different types of subsequent cyclizations to rapidly produce a variety of complicated chiral nitrogenand/or oxygen-containing heterocycles with diverse structural skeletons. Table 1 Substrate scope of alcoholsa
substrates, the desired three-component products were afforded in moderate yields with high dr and ee values (Table 1, entries 2 and 3). Allyl alcohol 2d also yielded the corresponding product in 82% yield with > 95:5 dr and 94% ee (Table 1, entry 4). Most strikingly, aliphatic alcohols bearing Boc-protected secondary amino functional groups like 2e and 2f also underwent the desired three-component transformation smoothly, affording corresponding products in high yields with excellent dr and high ee after slight modification of the reaction conditions (Table 1, entries 5 and 6). On the other hand, with furan-derived alcohol 2g as the substrate, the desired product was also obtained in good yield with excellent dr and high ee (Table 1, entry 7).13
Scheme 2 Proposed sequencing of enantioselective three-component reaction of 2h, 1a and 3a with one-pot subsequent cylization to synthesis chiral morpholines.
Entry 1 2 3 4 5e,f 6e,f 7e,f
2 2a 2b 2c 2d 2e 2f 2g
X 10 10 10 10 20 20 20
4 4a 4b 4c 4d 4e 4f 4g
Yield (%)b 70 66 52 82 89 83 83
Drc 94:6 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5
Ee (%)d 94 96 97 94 93 92 95
a
All reactions were conducted on a 0.1 mmol scale for 3a, 1a:2a:3a = 3:3:1. See the Supporting Information for experimental details. b Isolated yield after column chromatography. c Determined by 1H NMR of the crude mixture. d Determined by chiral HPLC, major diastereomer. e CH2Cl2 was used as the solvent instead of toluene. f Conducted at 0 oC. Chiral zirconium (IV) complexes of binaphthol have been widely used to catalyze N-arylaldimines for a variety of enantioselective transformations.9 We chose Zr(IV)-BINOL complex as a co-catalyst for Rh(II)-catalyzed three-component reaction of diazo compounds with alcohols and N-arylaldimines, with the hope that the o-hydroxyl group in the aldimine substrate would allow a stronger bidentate chelation with chiral zirconium complex and therefore give better stereoselective control in the oxonium ylide-trapping process. By choosing benzyl alcohol 2a and methyl phenyldiazoacetate 1a as the ylide precursors and Narylaldimine 3a as the electrophile, thorough reaction condition optimizations were conducted for this Rh(II)/chiral Zr(IV)-BINOL co-catalyzed three-component reaction.10 And the optimal conditions were achieved when 10 mol% of pre-prepared airstable Zr(IV) complex derived from (S)-3,3’-diiodo-BINOL (5d) in a 1:1 Zr( IV)/BINOL ratio with 3 Å MS (5d-ZrMS) was used as the co-catalyst,11 giving the desired three-component product 4a in 70% yield with 94:6 dr and 94% ee (Table 1, entry 1). The benzyl group as well as the o-hydroxyl phenolic N-substituent of the product 4a could be readily removed and therefore offered a convenient method for the synthesis of chiral α-hydroxyl-β-emino esters.12 This Rh(II)/chiral Zr(IV)-BINOL co-catalytic system showed superior scope of alcohols. When aliphatic alcohols such as nbutyl alcohol 2b or isopropyl alcohol 2c were used as the
2 | J. Name., 2012, 00, 1-3
The unique functionality tolerance feature of this rhodium/Zr(IV)-BINOL co-catalytic system encouraged us to develop sequencing of MCRs and subsequent cyclizations to rapidly synthesize chiral heterocycles. For example, by choosing 2-bromoethanol 2h as the substrate, a subsequent cyclization may occur from the resulting three-component product 4h to provide 2,2-disubstituted morpholines,14 which belong to an important class of structural motifs showing interesting medicinal applications (Scheme 2).15 Different methods including the use of Sharpless dihydroxylation (AD-mix β),16 asymmetric epoxidation of homoallylic alcohols17 or asymmetric cyanosilylation of ketones18 as key steps have been developed for the synthesis of optically active 2,2-disubstituted morpholines, however, most of these methods require multiple steps, whereas the proposed sequencing of three-component reaction and subsequent cyclization would be a highly rapid and efficient one for the synthesis of such compounds. To fulfil the designed one-pot transformation, 2-bromoethanol 2h was allowed to react with 1a and 3a under the standard Rh(II)/Zr(IV)-BINOL co-catalytic conditions. The desired threecomponent product was observed as the major one as detected by 1H NMR. Meanwhile, a small amount of simultaneously cyclized product 6a was also detected. To facilitate the subsequent cyclizing process, 5 equiv of triethylamine (TEA) was added in one-pot manner after completion of the threecomponent reaction, and 6a was obtained as the major product in 60% yield with 91:9 dr and 94% ee (Table 2, entry 1).19 In view of the intestering structural properties of the resulted 2,2-disubstituted morpholines, we investigated the substrate scope of this one-pot sequecing transformation. Different substituted N-arylaldimines were first investigated. With different para-substituents on the aryl group, the corresponding products were produced in moderate to good yields with high to excellent dr and ee regardless of their electronic effects (Table 2, entries 2–9). When meta- or ortho-halogenated aryl groups were used,
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the desired morpholine products were also obtained in good results (Table 2, entries 10–13). With 3,4-methylenedioxysubstituted substrate, the desired product 6n was produced with slightly reduced dr and ee (Table 2, entry 14). 2-naphthyl substituted substrate also gave the desired product 6m in high dr and ee (Table 2, entry 15). In addition to α-aryl diazoacetates, αalkyl diazoacetate 1d was also applicable to this one-pot transformation, providing the corresponding product 6r in 58% yield with 93:7 dr and 87% ee (Table 2, entries 18).
addition of two equivalents of AlCl3 (Scheme 3, eq 2). The ethyl ester group of 8 was readily hydrolyzed to the corresponding acid 9. And the absolute stereochemistry of 8 was determined by X-ray crystal analysis of racemic 9 as well as by analogy with the absolute stereochemistry of 4a. N2
HN
Ph
CO2Me
O
1a
N
Table 2. Realization and scope of three-component reaction with one-pot subsequent cylization to synthesize chiral morpholinesa
N
Ar
OH
O
Br
2i
3e Ar = o-OH-C6H4
1) Rh2(OAc)4 (1 mol%) 5d-ZrMs (20 mol%) CHCl3, 0 oC 2) NH2NH2/H2O, EtOH
O
O
Ph NH Ar
Br
(1)
7 62% 95:5 dr; 97% ee EtO2C
EtO2C
OH
2j N2 Ph
1a
Entry
1
Ar1
6
1 2 3 4 5 6 7 8 9 10 11 12 13e 14 15 16 17 18e,f
1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1b 1c 1d
Ph p-Me-Ph p-MeO-Ph p-F-Ph p-Br-Ph p-Cl-Ph p-NO2-Ph p-CF3-Ph p-CN-Ph m-Cl-Ph m-Br-Ph o-F-Ph o-Br-Ph 3,4-(OCH2O)-Ph 2-naphthyl p-Br-Ph p-Br-Ph p-Br-Ph
6a 6b 6c 6d 6e 6f 6g 6h 6i 6j 6k 6l 6m 6n 6o 6p 6q 6r
Yield (%)b 60 69 71 83 63 80 65 63 70 67 67 64 51 59 77 59 57 58
Drc 91:9 94:6 93:7 >95:5 >95:5 >95:5 >95:5 >95:5 93:7 94:6 93:7 >95:5 >95:5 90:10 93:7 >95:5 93:7 93:7
Ee (%)d 94 93 85 92 94 93 92 90 90 90 89 92 89 76 91 75 70 87
a Unless otherwise noted, all reactions were conducted in 0.1 mmol scale of 3, 1:2h:3 = 3:3:1, TEA (5.0 equiv) was added after completion of the threecomponent reaction as monitored by TLC. b Isolated yield. c Determined by 1H NMR of crude mixture. d Determined by chiral HPLC, major diastereomer. e 20 mol% 5d-ZrMs was added. f Reaction conducted at 0 oC.
Encouraged by the successful development of the sequencing transformation starting from 2-bromoethanol 2h, we decided to expand the sequencing strategy to synthesize other chiral heterocycles with diverse skeletons. Therefore, 2phthalimidoethanol 2i was chosen to react with methyl phenyldiazoacetate 1a and N-aryl aldimine 3e. When the Rh2(OAc)4/Zr(IV)-BINOL co-catalyzed three-component reaction was finished, one-pot hydrazinolysis followed by intramolecular amide formation was successfully accomplished and morpholin3-one 7 was produced in 62% yield with 95:5 dr and 97% ee (Scheme 3, eq 1). On the other hand, (E)-ethyl 4-hydroxybut-2-enoate 2j was chosen as the alcohol source, hoping to establish a subsequent aza-Michael-type cyclization process. After optimizations of the one-pot conditions,19 the desired cyclized product 8 was obtained in 51% yield with 94:6 dr and 94% ee under standard Rh(II)/Zr(IV)-BINOL co-catalytic conditions followed by the
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N
+ CO2Me
Ph
Ar
3a
1) Rh2(OAc)4 (1 mol%) 5d-ZrMS (20 mol%) CHCl3, 0 oC 2) AlCl3 (2.0 equiv), rt, overnight
Ar = o-OH-C6H4
N O
Ar Ph
Ph
(2)
CO2Me
8 51% 95:5 dr; 94% ee Br
N2 MeO2C
CO2Me
1e
N
Ar
1) Rh2(OAc)4 (2 mol%) (R)-5d-ZrMs (20 mol%) BnO CHCl3, 0 oC MeO2C
BnOH
2a
Br
3e Ar = o-OH-C6H4
2) TFA 5 mol%, rt
H N Ar
(3)
10 O 65% 95:5 dr; 90% ee
Scheme 3 Sequencing of enantioselective three-component reactions with various one-pot subsequent cyclizations.
The advantage of the current strategy to make divergent chiral heterocycles is to easily produce different types of chiral heterocycles by just adapting a suitable starting component. For example, when the diazo component was extended to dimethyl 2-diazosuccinate 1e, reaction of 1e with benzyl alcohol 2a and aldimine 3e gave chiral γ-lactam 10 in 65% yield with 95:5 dr and 90% ee via the desired three-component reaction followed by an efficient one-pot γ-lactamination (Scheme 3, eq 3). More strikingly, different types of chiral heterocycles can be easily made when changing the aldimine component to an aldehyde under this Rh(II)/Zr(IV)-BINOL co-catalytic system.[11] For example, the three-component reaction of propargyl alcohol 2k, diazoacetate 1a and 4-bromobenzaldehyde 11 followed by a PtCl2-catalyzed cyclization gave 2,3-trisubstituted 1,4-dioxine 12 in 56% yield with 94:6 dr and 97% ee (Scheme 4, eq 4). The three-component reaction of cinnamaldehyde 13 with allylic alcohol 2d and diazoacetate 1a followed by ring-closing metathesis gave 2H-pyran 14 in 70% yield with 95:5 dr and 99% ee (Scheme 4, eq 5). These transformations showed not only the broad functionality tolerance of this co-catalytic system, but also its highly compatible feature with various subsequent cyclizing conditions. In summary, we have developed a highly efficient sequencing of catalytic asymmetric three-component reactions and subsequent cyclizations. With the robust and versatile Rh(II)/Zr(IV)-BINOL co-catalytic system, the three-component reaction of alcohols, diazo compounds and aldimines/aldehydes was achieved with excellent diastereo- and enantioselectivities,
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4. 5.
6. 7.
Scheme 4 Sequencing transformations starting from different aldehydes.
8.
We are grateful for financial supports from NSF of China (21125209, 21332003 and 201402051), the MOST of China (2011CB808600) and STCSM (12JC1403800). We thank Prof. R.-Y. Wang from Xian Jiaotong-Liverpool University for X-ray crystallographic analysis.
9.
Notes and references Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Chemical Engineering, East China Normal University, Shanghai, 200062, China E-mail: [email protected]; [email protected] † Electronic Supplementary Information (ESI) available: Information regarding materials and methods, characterization data of compounds from this study]. See DOI: 10.1039/c000000x/ 1. (a) Heterocyclic Chemistry in Drug Discovery, J. J. Li, Ed.; Wiley, Hoboken, NJ, 2013; (b) Heterocycles in Natural Product Synthsis, K. C. Majumdar, S. K. Chattopadhyay, Ed.; Wiley, Weinheim, Germany, 2011; (c) Stereoselective Synthesis of Drugs and Natural Products, V. Andrushko, N. Andrushko, Ed.; Wiley, Karlsruhe, Germany 2013. 2. For selected reviews, see: (a) M. D. Burke, S. L. Schreiber, Angew. Chem. Int. Ed. 2004, 43, 46; (b) D. S. Tan, Nat. Chem. Biol. 2005, 1, 74; (c) R. J. Spandl, A. Bender, D. R. Spring, Org. Biomol. Chem. 2008, 6, 1149; (d) J. D. Sunderhaus, S. F. Martin, Chem.--Eur. J. 2009, 15, 1300; (e) S. Dandapani, L. A. Marcaurelle, Curr. Opin. Chem. Biol. 2010, 14, 362; (f) W. Galloway, A. Isidro-Llobet, D. R. Spring, Nat. Commun. 2010, 1, 80;; (g) C. J. O' Connor, H. S. G. Beckmann, D. R. Spring, Chem. Soc. Rev. 2012, 41, 4444. 3. For selected reviews, see: (a) V. Nair, C. Rajesh, A. U. Vinod, S. Bindu, A. R. Sreekanth, J. S. Mathen, L. Balagopal, Acc. Chem. Res. 2003, 36, 899; (b) J. E. Biggs-Houck, A. Younai, J. T. Shaw, Curr. Opin. Chem. Biol. 2010, 14, 371; (c) E. Ruijter, R. Scheffelaar, R. V. A. Orru, Angew. Chem. Int. Ed. 2011, 50, 6234; (d) A. Dömling, W. Wang, K. Wang, Chem. Rev. 2012, 112, 3083; (e) F. Lorenzini, J. Tjutrins, J. S. Quesnel, B. A. Arndtsen, in Multicomponent Reactions in Organic Synthesis, (Ed.: J. Zhu, Q. Wang, M. Wang), Wiley,
4 | J. Name., 2012, 00, 1-3
10. 11.
12. 13.
14.
15.
16. 17. 18. 19. 20.
Weinheim, 2014, chap. 8, pp.207-227; (f) P. K. Maji, R. Ul Islam, S. K. Bera, Heterocycles 2014, 89, 869-962. See references 2d, 2e and references cited therein. For recent leading reviews on metal carbenes, see: a) A.-H. Li, L.-X. Dai, V. K. Aggarwal, Chem. Rev. 1997, 97, 2341; b) M. P. Doyle, D. C. Forbes, Chem. Rev. 1998, 98, 911; c) H. M. L. Davies, J. R. Manning, Nature 2008, 451, 417; d) S.-F. Zhu, Q.-L. Zhou, Acc. Chem. Res. 2012, 45, 1365; e) X. Zhao, Y. Zhang, J. Wang, Chem. Commun. 2012, 48, 10162. X. Guo, W. Hu, Acc. Chem. Res. 2013, 46, 2427. For selected examples developed by our group, see: (a) W. H. Hu, X. F. Xu, J. Zhou, W. J. Liu, H. X. Huang, J. Hu, L. P. Yang, L. Z. Gong, J. Am. Chem. Soc. 2008, 130, 7782; (b) X. Zhang, H. Huang, X. Guo, X. Guan, L. Yang, W. Hu, Angew. Chem. Int. Ed. 2008, 47, 6647; (c) J. Jiang, H.-D. Xu, J.-B. Xi, B.-Y. Ren, F.-P. Lv, X. Guo, L.-Q. Jiang, Z.-Y. Zhang, W.-H. Hu, J. Am. Chem. Soc. 2011, 133, 8428. For examples developed by others, see: (a) C.-Y. Zhou, J.-C. Wang, J. Wei, Z.-J. Xu, Z. Guo, K.-H. Low, C.-M. Che, Angew. Chem. Int. Ed. 2012, 51, 11376; (b) L. Ren, X.-L. Lian, L.-Z. Gong, Chem.-Eur. J. 2013, 19, 3315. For reviews and selected examples, see: (a) S. Kobayashi, H. Ishitani, Chem. Rev. 1999, 99, 1069; (b) S. Kobayashi, Y. Mori, J. S. Fossey, M. M. Salter, Chem. Rev. 2011, 111, 2626; (c) S. Kobayashi, M. Ueno, S. Saito, Y. Mizuki, H. Ishitani, Y. Yamashita, Proc. Natl. Acad. Sci. 2004, 101, 5476; (d) Y. Ihori, Y. Yamashita, H. Ishitani, S. Kobayashi, J. Am. Chem. Soc. 2005, 127, 15528. For detailed condition optimizations and preparation of catalysts, see the Supporting Information. Zr(IV)-BINOL complex pre-prepared in a 1:1 Zr(IV)/BINOL ratio has only been reported to activate aldehydes for high enantioselective aldol-type reactions, see: Y. Yamashita, H. Ishitani, H. Shimizu, S. Kobayashi, J. Am. Chem. Soc. 2002, 124, 3292. For detailed synthetic procedures, see the Supporting Information. The absolute configuration of products was assigned in analogy with 4a, which was determined as (2S,3S) by converting it into a known compound and comparison of its optical rotation with literature. For details, see the Supporting Information. For the synthesis of morpholines from halogen-functionalized βamino ethers, see: (a) L. Zhou, C. K. Tan, J. Zhou, Y.-Y. Yeung, J. Am. Chem. Soc. 2010, 132, 10245; (b) J. Zhou, L. Zhou, Y.-Y. Yeung, Org. Lett. 2012, 14, 5250. (a) R. Wijtmans, M. K. S. Vink, H. E. Schoemaker, F. L. van Delft, R. H. Blaauw, F. Rutjes, Synthesis 2004, 641; (b) E. A. Rekka, P. N. Kourounakis, Curr. Med. Chem. 2010, 17, 3422. T. Nishi, K. Nakajima, Y. Iio, K. Ishibashi, T. Fukazawa, Tetrahedron: Asymmetry 1998, 9, 2567. T. Okachi, N. Murai, M. Onaka, Org. Lett. 2003, 5, 85. M. Takamura, K. Yabu, T. Nishi, H. Yanagisawa, M. Kanai, M. Shibasaki, Synlett 2003, 2003, 353. Condition optimization revealed that the use of 15 mol% 7d-ZrMS gave the best results. For details, see the Supporting Information. For details, see the Supporting Information.
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COMMUNICATION and thanks to the high functional group tolerance feature of this catalytic system, a variety of subsequent cyclizations readily occur through different pre-installed functional groups in each component, thus providing rapid and diversity-oriented synthesis (DOS) of an array of chiral nitrogen- and/or oxygen-containing polyfunctional heterocycles.
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This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.
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Divergent Synthesis of Chiral Heterocycles via Sequencing of Enantioselective Three-Component Reactions and One-Pot Subsequent Cyclizations Min Tang, Dong Xing,* Haoxi Huang and Wenhao Hu*
Received 00th January 2012, Accepted 00th January 2012 DOI: 10.1039/x0xx00000x www.rsc.org/
A highly efficient sequencing of catalytic asymmetric threecomponent reactions of alcohols, diazo compounds and aldimines/aldehydes with one-pot subsequent cyclizations was reported. The development of a robust and versatile Rh(II)/Zr(IV)-BINOL co-catalytic system not only gives high diastereo- and enantioselective controls of the threecomponent reaction, but also show excellent functionality tolerances that allow a wide range of functionalities to be preinstalled in each component and readily undergo one-pot subsequent cyclizations, thus providing rapid and diversityoriented synthesis (DOS) of different types of chiral nitrogenand/or oxygen-containing polyfunctional heterocycles. Nitrogen- and/or oxygen-containing chiral heterocycles are inarguably among the most abundant structural motifs in biologically active natural products and pharmaceuticals.1 As a result, there has been an increasing demand for chemical libraries of chiral heterocycles in drug discovery process and chemical biological studies. Synthetic strategies for the rapid construction of collections of structurally diverse heterocycles, such as diversity-oriented synthesis (DOS) 2 or multicomponent reactions (MCRs),3 have drawn considerable attention from the synthetic community. Among them, the sequencing of MCRs with subsequent cyclizations, which relies on each component of the MCR to incorporate different functionalities to undergo subsequent cyclizations through functional group pairing, is one of the most promising synthetic strategies for such purpose.2d,2e,3b However, although a number of MCRs have been successfully applied to this sequencing strategy,4 to the best of our knowledge, there are currently no catalytic asymmetric examples of such transformations for the rapid construction of collections of chiral heterocycles. The challenge in realizing this kind of transformations might attribute to the difficulty in discovering a robust catalytic system in enantioselective multi-component
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reactions that can not only provide efficient diastereo- and enantioselective controls, but also show excellent functionality tolerance so different functional groups responsible for subsequent cyclizations could be pre-installed on each component and well tolerated without compromising stereoselectivities (Scheme 1).
Scheme 1 Concept for sequencing enantioselective multi-component reactions with one-pot subsequent cyclizations to generate diverse chiral heterocycles.
As part of our continuous research efforts in developing catalytic asymmetric MCRs through electrophilic trapping of active onium ylides generated from metal carbenes,5-8 we aimed at exploring catalytic systems for such types of MCRs that can not only give efficient stereoselective controls but also show high functionality tolerance for subsequent cyclizations, therefore offering efficient strategies for the rapid construction of versatile chiral heterocycles. We turned our attention to the threecomponent reaction of diazo compounds with alcohols and imines, hoping that the generated chiral β-amino alcohol product would be an ideal structural motif to undergo subsequent cyclization to give various nitrogen- and/or oxygen-containing heterocycles via suitable functional groups pairing strategies. Herein, we report our successful development of a rhodium(II)/Zr(IV)-BINOL co-catalytic system for highly diastereoand enantioselective three-component reaction of diazo
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compounds with alcohols and imines/aldehydes. Taking advantage of the robust co-catalytic system, substrates bearing different pre-installed functionalities readily underwent the sequencing of three-component reactions and different types of subsequent cyclizations to rapidly produce a variety of complicated chiral nitrogenand/or oxygen-containing heterocycles with diverse structural skeletons. Table 1 Substrate scope of alcoholsa
substrates, the desired three-component products were afforded in moderate yields with high dr and ee values (Table 1, entries 2 and 3). Allyl alcohol 2d also yielded the corresponding product in 82% yield with > 95:5 dr and 94% ee (Table 1, entry 4). Most strikingly, aliphatic alcohols bearing Boc-protected secondary amino functional groups like 2e and 2f also underwent the desired three-component transformation smoothly, affording corresponding products in high yields with excellent dr and high ee after slight modification of the reaction conditions (Table 1, entries 5 and 6). On the other hand, with furan-derived alcohol 2g as the substrate, the desired product was also obtained in good yield with excellent dr and high ee (Table 1, entry 7).13
Scheme 2 Proposed sequencing of enantioselective three-component reaction of 2h, 1a and 3a with one-pot subsequent cylization to synthesis chiral morpholines.
Entry 1 2 3 4 5e,f 6e,f 7e,f
2 2a 2b 2c 2d 2e 2f 2g
X 10 10 10 10 20 20 20
4 4a 4b 4c 4d 4e 4f 4g
Yield (%)b 70 66 52 82 89 83 83
Drc 94:6 >95:5 >95:5 >95:5 >95:5 >95:5 >95:5
Ee (%)d 94 96 97 94 93 92 95
a
All reactions were conducted on a 0.1 mmol scale for 3a, 1a:2a:3a = 3:3:1. See the Supporting Information for experimental details. b Isolated yield after column chromatography. c Determined by 1H NMR of the crude mixture. d Determined by chiral HPLC, major diastereomer. e CH2Cl2 was used as the solvent instead of toluene. f Conducted at 0 oC. Chiral zirconium (IV) complexes of binaphthol have been widely used to catalyze N-arylaldimines for a variety of enantioselective transformations.9 We chose Zr(IV)-BINOL complex as a co-catalyst for Rh(II)-catalyzed three-component reaction of diazo compounds with alcohols and N-arylaldimines, with the hope that the o-hydroxyl group in the aldimine substrate would allow a stronger bidentate chelation with chiral zirconium complex and therefore give better stereoselective control in the oxonium ylide-trapping process. By choosing benzyl alcohol 2a and methyl phenyldiazoacetate 1a as the ylide precursors and Narylaldimine 3a as the electrophile, thorough reaction condition optimizations were conducted for this Rh(II)/chiral Zr(IV)-BINOL co-catalyzed three-component reaction.10 And the optimal conditions were achieved when 10 mol% of pre-prepared airstable Zr(IV) complex derived from (S)-3,3’-diiodo-BINOL (5d) in a 1:1 Zr( IV)/BINOL ratio with 3 Å MS (5d-ZrMS) was used as the co-catalyst,11 giving the desired three-component product 4a in 70% yield with 94:6 dr and 94% ee (Table 1, entry 1). The benzyl group as well as the o-hydroxyl phenolic N-substituent of the product 4a could be readily removed and therefore offered a convenient method for the synthesis of chiral α-hydroxyl-β-emino esters.12 This Rh(II)/chiral Zr(IV)-BINOL co-catalytic system showed superior scope of alcohols. When aliphatic alcohols such as nbutyl alcohol 2b or isopropyl alcohol 2c were used as the
2 | J. Name., 2012, 00, 1-3
The unique functionality tolerance feature of this rhodium/Zr(IV)-BINOL co-catalytic system encouraged us to develop sequencing of MCRs and subsequent cyclizations to rapidly synthesize chiral heterocycles. For example, by choosing 2-bromoethanol 2h as the substrate, a subsequent cyclization may occur from the resulting three-component product 4h to provide 2,2-disubstituted morpholines,14 which belong to an important class of structural motifs showing interesting medicinal applications (Scheme 2).15 Different methods including the use of Sharpless dihydroxylation (AD-mix β),16 asymmetric epoxidation of homoallylic alcohols17 or asymmetric cyanosilylation of ketones18 as key steps have been developed for the synthesis of optically active 2,2-disubstituted morpholines, however, most of these methods require multiple steps, whereas the proposed sequencing of three-component reaction and subsequent cyclization would be a highly rapid and efficient one for the synthesis of such compounds. To fulfil the designed one-pot transformation, 2-bromoethanol 2h was allowed to react with 1a and 3a under the standard Rh(II)/Zr(IV)-BINOL co-catalytic conditions. The desired threecomponent product was observed as the major one as detected by 1H NMR. Meanwhile, a small amount of simultaneously cyclized product 6a was also detected. To facilitate the subsequent cyclizing process, 5 equiv of triethylamine (TEA) was added in one-pot manner after completion of the threecomponent reaction, and 6a was obtained as the major product in 60% yield with 91:9 dr and 94% ee (Table 2, entry 1).19 In view of the intestering structural properties of the resulted 2,2-disubstituted morpholines, we investigated the substrate scope of this one-pot sequecing transformation. Different substituted N-arylaldimines were first investigated. With different para-substituents on the aryl group, the corresponding products were produced in moderate to good yields with high to excellent dr and ee regardless of their electronic effects (Table 2, entries 2–9). When meta- or ortho-halogenated aryl groups were used,
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the desired morpholine products were also obtained in good results (Table 2, entries 10–13). With 3,4-methylenedioxysubstituted substrate, the desired product 6n was produced with slightly reduced dr and ee (Table 2, entry 14). 2-naphthyl substituted substrate also gave the desired product 6m in high dr and ee (Table 2, entry 15). In addition to α-aryl diazoacetates, αalkyl diazoacetate 1d was also applicable to this one-pot transformation, providing the corresponding product 6r in 58% yield with 93:7 dr and 87% ee (Table 2, entries 18).
addition of two equivalents of AlCl3 (Scheme 3, eq 2). The ethyl ester group of 8 was readily hydrolyzed to the corresponding acid 9. And the absolute stereochemistry of 8 was determined by X-ray crystal analysis of racemic 9 as well as by analogy with the absolute stereochemistry of 4a. N2
HN
Ph
CO2Me
O
1a
N
Table 2. Realization and scope of three-component reaction with one-pot subsequent cylization to synthesize chiral morpholinesa
N
Ar
OH
O
Br
2i
3e Ar = o-OH-C6H4
1) Rh2(OAc)4 (1 mol%) 5d-ZrMs (20 mol%) CHCl3, 0 oC 2) NH2NH2/H2O, EtOH
O
O
Ph NH Ar
Br
(1)
7 62% 95:5 dr; 97% ee EtO2C
EtO2C
OH
2j N2 Ph
1a
Entry
1
Ar1
6
1 2 3 4 5 6 7 8 9 10 11 12 13e 14 15 16 17 18e,f
1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1b 1c 1d
Ph p-Me-Ph p-MeO-Ph p-F-Ph p-Br-Ph p-Cl-Ph p-NO2-Ph p-CF3-Ph p-CN-Ph m-Cl-Ph m-Br-Ph o-F-Ph o-Br-Ph 3,4-(OCH2O)-Ph 2-naphthyl p-Br-Ph p-Br-Ph p-Br-Ph
6a 6b 6c 6d 6e 6f 6g 6h 6i 6j 6k 6l 6m 6n 6o 6p 6q 6r
Yield (%)b 60 69 71 83 63 80 65 63 70 67 67 64 51 59 77 59 57 58
Drc 91:9 94:6 93:7 >95:5 >95:5 >95:5 >95:5 >95:5 93:7 94:6 93:7 >95:5 >95:5 90:10 93:7 >95:5 93:7 93:7
Ee (%)d 94 93 85 92 94 93 92 90 90 90 89 92 89 76 91 75 70 87
a Unless otherwise noted, all reactions were conducted in 0.1 mmol scale of 3, 1:2h:3 = 3:3:1, TEA (5.0 equiv) was added after completion of the threecomponent reaction as monitored by TLC. b Isolated yield. c Determined by 1H NMR of crude mixture. d Determined by chiral HPLC, major diastereomer. e 20 mol% 5d-ZrMs was added. f Reaction conducted at 0 oC.
Encouraged by the successful development of the sequencing transformation starting from 2-bromoethanol 2h, we decided to expand the sequencing strategy to synthesize other chiral heterocycles with diverse skeletons. Therefore, 2phthalimidoethanol 2i was chosen to react with methyl phenyldiazoacetate 1a and N-aryl aldimine 3e. When the Rh2(OAc)4/Zr(IV)-BINOL co-catalyzed three-component reaction was finished, one-pot hydrazinolysis followed by intramolecular amide formation was successfully accomplished and morpholin3-one 7 was produced in 62% yield with 95:5 dr and 97% ee (Scheme 3, eq 1). On the other hand, (E)-ethyl 4-hydroxybut-2-enoate 2j was chosen as the alcohol source, hoping to establish a subsequent aza-Michael-type cyclization process. After optimizations of the one-pot conditions,19 the desired cyclized product 8 was obtained in 51% yield with 94:6 dr and 94% ee under standard Rh(II)/Zr(IV)-BINOL co-catalytic conditions followed by the
This journal is © The Royal Society of Chemistry 2012
N
+ CO2Me
Ph
Ar
3a
1) Rh2(OAc)4 (1 mol%) 5d-ZrMS (20 mol%) CHCl3, 0 oC 2) AlCl3 (2.0 equiv), rt, overnight
Ar = o-OH-C6H4
N O
Ar Ph
Ph
(2)
CO2Me
8 51% 95:5 dr; 94% ee Br
N2 MeO2C
CO2Me
1e
N
Ar
1) Rh2(OAc)4 (2 mol%) (R)-5d-ZrMs (20 mol%) BnO CHCl3, 0 oC MeO2C
BnOH
2a
Br
3e Ar = o-OH-C6H4
2) TFA 5 mol%, rt
H N Ar
(3)
10 O 65% 95:5 dr; 90% ee
Scheme 3 Sequencing of enantioselective three-component reactions with various one-pot subsequent cyclizations.
The advantage of the current strategy to make divergent chiral heterocycles is to easily produce different types of chiral heterocycles by just adapting a suitable starting component. For example, when the diazo component was extended to dimethyl 2-diazosuccinate 1e, reaction of 1e with benzyl alcohol 2a and aldimine 3e gave chiral γ-lactam 10 in 65% yield with 95:5 dr and 90% ee via the desired three-component reaction followed by an efficient one-pot γ-lactamination (Scheme 3, eq 3). More strikingly, different types of chiral heterocycles can be easily made when changing the aldimine component to an aldehyde under this Rh(II)/Zr(IV)-BINOL co-catalytic system.[11] For example, the three-component reaction of propargyl alcohol 2k, diazoacetate 1a and 4-bromobenzaldehyde 11 followed by a PtCl2-catalyzed cyclization gave 2,3-trisubstituted 1,4-dioxine 12 in 56% yield with 94:6 dr and 97% ee (Scheme 4, eq 4). The three-component reaction of cinnamaldehyde 13 with allylic alcohol 2d and diazoacetate 1a followed by ring-closing metathesis gave 2H-pyran 14 in 70% yield with 95:5 dr and 99% ee (Scheme 4, eq 5). These transformations showed not only the broad functionality tolerance of this co-catalytic system, but also its highly compatible feature with various subsequent cyclizing conditions. In summary, we have developed a highly efficient sequencing of catalytic asymmetric three-component reactions and subsequent cyclizations. With the robust and versatile Rh(II)/Zr(IV)-BINOL co-catalytic system, the three-component reaction of alcohols, diazo compounds and aldimines/aldehydes was achieved with excellent diastereo- and enantioselectivities,
J. Name., 2012, 00, 1-3 | 3
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4. 5.
6. 7.
Scheme 4 Sequencing transformations starting from different aldehydes.
8.
We are grateful for financial supports from NSF of China (21125209, 21332003 and 201402051), the MOST of China (2011CB808600) and STCSM (12JC1403800). We thank Prof. R.-Y. Wang from Xian Jiaotong-Liverpool University for X-ray crystallographic analysis.
9.
Notes and references Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Chemical Engineering, East China Normal University, Shanghai, 200062, China E-mail: [email protected]; [email protected] † Electronic Supplementary Information (ESI) available: Information regarding materials and methods, characterization data of compounds from this study]. See DOI: 10.1039/c000000x/ 1. (a) Heterocyclic Chemistry in Drug Discovery, J. J. Li, Ed.; Wiley, Hoboken, NJ, 2013; (b) Heterocycles in Natural Product Synthsis, K. C. Majumdar, S. K. Chattopadhyay, Ed.; Wiley, Weinheim, Germany, 2011; (c) Stereoselective Synthesis of Drugs and Natural Products, V. Andrushko, N. Andrushko, Ed.; Wiley, Karlsruhe, Germany 2013. 2. For selected reviews, see: (a) M. D. Burke, S. L. Schreiber, Angew. Chem. Int. Ed. 2004, 43, 46; (b) D. S. Tan, Nat. Chem. Biol. 2005, 1, 74; (c) R. J. Spandl, A. Bender, D. R. Spring, Org. Biomol. Chem. 2008, 6, 1149; (d) J. D. Sunderhaus, S. F. Martin, Chem.--Eur. J. 2009, 15, 1300; (e) S. Dandapani, L. A. Marcaurelle, Curr. Opin. Chem. Biol. 2010, 14, 362; (f) W. Galloway, A. Isidro-Llobet, D. R. Spring, Nat. Commun. 2010, 1, 80;; (g) C. J. O' Connor, H. S. G. Beckmann, D. R. Spring, Chem. Soc. Rev. 2012, 41, 4444. 3. For selected reviews, see: (a) V. Nair, C. Rajesh, A. U. Vinod, S. Bindu, A. R. Sreekanth, J. S. Mathen, L. Balagopal, Acc. Chem. Res. 2003, 36, 899; (b) J. E. Biggs-Houck, A. Younai, J. T. Shaw, Curr. Opin. Chem. Biol. 2010, 14, 371; (c) E. Ruijter, R. Scheffelaar, R. V. A. Orru, Angew. Chem. Int. Ed. 2011, 50, 6234; (d) A. Dömling, W. Wang, K. Wang, Chem. Rev. 2012, 112, 3083; (e) F. Lorenzini, J. Tjutrins, J. S. Quesnel, B. A. Arndtsen, in Multicomponent Reactions in Organic Synthesis, (Ed.: J. Zhu, Q. Wang, M. Wang), Wiley,
4 | J. Name., 2012, 00, 1-3
10. 11.
12. 13.
14.
15.
16. 17. 18. 19. 20.
Weinheim, 2014, chap. 8, pp.207-227; (f) P. K. Maji, R. Ul Islam, S. K. Bera, Heterocycles 2014, 89, 869-962. See references 2d, 2e and references cited therein. For recent leading reviews on metal carbenes, see: a) A.-H. Li, L.-X. Dai, V. K. Aggarwal, Chem. Rev. 1997, 97, 2341; b) M. P. Doyle, D. C. Forbes, Chem. Rev. 1998, 98, 911; c) H. M. L. Davies, J. R. Manning, Nature 2008, 451, 417; d) S.-F. Zhu, Q.-L. Zhou, Acc. Chem. Res. 2012, 45, 1365; e) X. Zhao, Y. Zhang, J. Wang, Chem. Commun. 2012, 48, 10162. X. Guo, W. Hu, Acc. Chem. Res. 2013, 46, 2427. For selected examples developed by our group, see: (a) W. H. Hu, X. F. Xu, J. Zhou, W. J. Liu, H. X. Huang, J. Hu, L. P. Yang, L. Z. Gong, J. Am. Chem. Soc. 2008, 130, 7782; (b) X. Zhang, H. Huang, X. Guo, X. Guan, L. Yang, W. Hu, Angew. Chem. Int. Ed. 2008, 47, 6647; (c) J. Jiang, H.-D. Xu, J.-B. Xi, B.-Y. Ren, F.-P. Lv, X. Guo, L.-Q. Jiang, Z.-Y. Zhang, W.-H. Hu, J. Am. Chem. Soc. 2011, 133, 8428. For examples developed by others, see: (a) C.-Y. Zhou, J.-C. Wang, J. Wei, Z.-J. Xu, Z. Guo, K.-H. Low, C.-M. Che, Angew. Chem. Int. Ed. 2012, 51, 11376; (b) L. Ren, X.-L. Lian, L.-Z. Gong, Chem.-Eur. J. 2013, 19, 3315. For reviews and selected examples, see: (a) S. Kobayashi, H. Ishitani, Chem. Rev. 1999, 99, 1069; (b) S. Kobayashi, Y. Mori, J. S. Fossey, M. M. Salter, Chem. Rev. 2011, 111, 2626; (c) S. Kobayashi, M. Ueno, S. Saito, Y. Mizuki, H. Ishitani, Y. Yamashita, Proc. Natl. Acad. Sci. 2004, 101, 5476; (d) Y. Ihori, Y. Yamashita, H. Ishitani, S. Kobayashi, J. Am. Chem. Soc. 2005, 127, 15528. For detailed condition optimizations and preparation of catalysts, see the Supporting Information. Zr(IV)-BINOL complex pre-prepared in a 1:1 Zr(IV)/BINOL ratio has only been reported to activate aldehydes for high enantioselective aldol-type reactions, see: Y. Yamashita, H. Ishitani, H. Shimizu, S. Kobayashi, J. Am. Chem. Soc. 2002, 124, 3292. For detailed synthetic procedures, see the Supporting Information. The absolute configuration of products was assigned in analogy with 4a, which was determined as (2S,3S) by converting it into a known compound and comparison of its optical rotation with literature. For details, see the Supporting Information. For the synthesis of morpholines from halogen-functionalized βamino ethers, see: (a) L. Zhou, C. K. Tan, J. Zhou, Y.-Y. Yeung, J. Am. Chem. Soc. 2010, 132, 10245; (b) J. Zhou, L. Zhou, Y.-Y. Yeung, Org. Lett. 2012, 14, 5250. (a) R. Wijtmans, M. K. S. Vink, H. E. Schoemaker, F. L. van Delft, R. H. Blaauw, F. Rutjes, Synthesis 2004, 641; (b) E. A. Rekka, P. N. Kourounakis, Curr. Med. Chem. 2010, 17, 3422. T. Nishi, K. Nakajima, Y. Iio, K. Ishibashi, T. Fukazawa, Tetrahedron: Asymmetry 1998, 9, 2567. T. Okachi, N. Murai, M. Onaka, Org. Lett. 2003, 5, 85. M. Takamura, K. Yabu, T. Nishi, H. Yanagisawa, M. Kanai, M. Shibasaki, Synlett 2003, 2003, 353. Condition optimization revealed that the use of 15 mol% 7d-ZrMS gave the best results. For details, see the Supporting Information. For details, see the Supporting Information.
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COMMUNICATION and thanks to the high functional group tolerance feature of this catalytic system, a variety of subsequent cyclizations readily occur through different pre-installed functional groups in each component, thus providing rapid and diversity-oriented synthesis (DOS) of an array of chiral nitrogen- and/or oxygen-containing polyfunctional heterocycles.
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