Letter pubs.acs.org/OrgLett
Catalyst-Enabled Scaffold Diversity: Highly Chemo- and Stereoselective Synthesis of Tricyclic Ketals and Triarylmethanes Jia-Yu Liao, Qijian Ni, and Yu Zhao* Department of Chemistry, National University of Singapore, 3 Science Drive 3, Republic of Singapore, 117543 S Supporting Information *
ABSTRACT: The first catalytic cascade reaction of activated isocyanides with para-quinone methide-aryl esters is presented. Catalyst-enabled divergent pathways have also been achieved to deliver skeletally diverse products. While Ag catalysis leads to an unprecedented highly diastereoselective synthesis of tricyclic ketals, a simple procedure employing Cu catalysis produces oxazole-containing triarylmethanes in high efficiency through an unexpected C−C bond cleavage.
fficient access to structurally complex compounds, especially those with scaffold diversity, is a crucial requirement for biological screening in drug discovery.1 Diversity-oriented or collective synthesis has been successfully practiced to generate skeletally diverse compounds through stepwise, divergent chemical transformations of central core intermediates.2,3 In catalytic method development, the realization of catalyst-enabled divergent reactivities has attracted much attention in recent years as well.4 The adoption of different catalytic conditions could lead to chemo-, regio-, or stereoselective transformations of the starting materials delivering isomeric products with similar frameworks (e.g., regio- or stereoisomers). More importantly, elegant reports on “productselective catalysis”4 were also documented in the literature, by which skeletally distinct compounds could be accessed.5 Despite these important advancements on this topic, the implementation of new strategies of catalyst-enabled transformations to achieve scaffold diversity remains an important goal in organic synthesis. Activated isocyanides, such as isocyanoacetates, are intriguing molecules bearing multiple reactive sites, which have found wide application in heterocycle synthesis.6,7 With our continuous interest and efforts in isocyanoacetate chemistry,8 we wondered whether isocyanoacetate 2 could serve as a perfect building block to introduce multiple functionalities if conjugate addition of 2 to para-quinone methide-aryl ester 19 could be realized. para-Quinone methides (p-QMs) have proven to be a powerful Michael acceptor for 1,6-addition reactions with a wide range of nucleophiles.10,11 We proposed that the addition of 2 to 1 should proceed efficiently to yield the phenol intermediate 3. Based on our previous discovery of oxazole formation from aryl esters and isocyanoacetates,8a we envisioned that an acyl transfer could take place next to yield the key intermediate 4, in which three different electrophiles (isocyanide, ketone, and ester) are attached on the same carbon, while the phenol unit
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© 2017 American Chemical Society
may serve as the nucleophile to undergo reaction with any one of the three. If chemoselectivity could be achieved under different catalytic conditions, further cascade intramolecular couplings could follow to deliver structurally diverse compounds (Scheme 1). For example, the addition of phenol to the isocyanide moiety Scheme 1. Catalyst-Enabled Scaffold Diversity
might lead to the formation of 1,3-oxazepines 5 (pathway i). Alternatively, the attack of the phenol to the ester moiety could form δ-lactones 7 (pathway iii). The focus of this study was whether efficient catalytic methods could be developed to realize such divergent transformations, ideally in a cascade fashion.12 We report herein the realization of this strategy to deliver two Received: June 17, 2017 Published: July 14, 2017 4074
DOI: 10.1021/acs.orglett.7b01851 Org. Lett. 2017, 19, 4074−4077
Letter
Organic Letters
With the optimal reaction conditions in hand, we moved on to explore the scope of the silver-catalyzed cascade cyclization for tricyclic ketal formation first (Scheme 2). As shown, excellent
unexpected scaffolds of tricyclic ketals 6 by attack on the ketone moiety in pathway ii, and triarylmethanes 8 through an intriguing C−C bond cleavage. The use of either Ag- or Cu-based catalyst proved to be the key for the chemoselectivity in these processes.13 We initiated our investigation using 1a and 2a as the model substrates. The selected key results of extensive catalyst screening are summarized in Table 1. On the basis of our
Scheme 2. Ag-Catalyzed Tricyclic Ketal Synthesisa,b
Table 1. Identification of Divergent Reaction Profilea
entry
metal/ligand
6a/8ab
6a yield (%)c
8a yield (%)c
1 2d 3 4 5
Ag2O/PPh3 Ag2O/PPh3 Cu(OAc)2/PPh3 Cu(OAc)2/dppm Cu(OAc)2/dppp
>20:1 >20:1 1.3:1 1.4:1 1:>20
95 94 n.d. n.d. 20:1 dr). When the catalyst was switched to Cu(OAc)2, intriguingly, an unexpected product triarylmethane 8a was observed, albeit in a mixture with 6a (entry 3, 6a/8a = 1.3:1). From the viewpoint of molecular structure, this type of compound is clearly formed through pathway iii. However, instead of the expected C−O bond cleavage to produce δ-lactones 7 (Scheme 1), an unexpected C−C bond cleavage occurred exclusively to generate the carbonate moiety followed by cyclization to deliver the triarylmethane scaffold. This observation of switchable chemoselectivity with Ag or Cu catalysis represents an interesting example of catalyst-enabled chemodivergent reactions,4 which could be caused by the different mode of coordination of the intermediate with these two metals. Recognizing that this unexpected reactivity catalyzed by copper provides a new entry to the difficult-to-access oxazole-containing triarylmethanes,14 we screened various readily available bisphosphine ligands to improve the efficiency of 8a formation. Although many ligands including dppm led to similarly low selectivity (entry 4, 6a/8a = 1.4:1), the use of dppp resulted in the exclusive formation of 8a with >98% isolated yield (entry 5). With the efficient formation of 6a or 8a in hand, we further screened other metal salts in an attempt to achieve the formation of pathway i product 5a. Unfortunately, no reactivity was obtained with the use of Co, Zn, Fe, Ni, or Au salts (see Supporting Information for details).
a,b See Table 1. cCarried out for 48 h. dIn this case, 6o and the corresponding triarylmethane were obtained in a ratio of 9:1.
diastereoselectivity (>20:1 dr) was obtained for product 6 in all cases. Different substitution patterns on the aryl ring (para-, meta-, and ortho-) could be well adopted to form 6a−6h in excellent selectivities and yields (87% to >98%). The variation on the ester moiety in 1 (bearing both alkyl and aryl substituents) was also tolerated to produce 6i−6l in uniformly excellent yields with excellent selectivities. Different isocyanoacetates could also be used to produce 6m and 6n in excellent yields and selectivities. The relative configuration of 6a was unambiguously assigned by single crystal X-ray analysis, and those of other tricyclic ketals were assigned by analogy. To further extend the substrate scope, isocyanoacetamide was examined under the standard conditions. To our delight, the desired product 6o was obtained in 75% yield, although a small amount of the corresponding triarylmethane product was formed in this case. The relative configuration of 6o proved to be the same as the other compounds by single crystal X-ray analysis. It is noteworthy that tricyclic ketals are important structural motifs in medicinal chemistry.15 This catalytic system can prepare such compounds with a “mix and go” procedure using commercially available and inexpensive Ag2O/PPh3 as catalysts. The reactions were set up open to air with no need for exclusion of air or moisture. In addition, this process is entirely atomeconomical as the product incorporates all portions from the substrates. The scope of the copper-catalyzed synthesis of triarylmethanes was examined next (Scheme 3). In almost all cases, excellent chemoselectivity and yield were obtained for product 8. Different substituents (electron-donating, electron-neutral, and electronwithdrawing) with diverse substitution patterns (para-, meta-, and ortho-) on the aryl ring could be well tolerated to deliver 4075
DOI: 10.1021/acs.orglett.7b01851 Org. Lett. 2017, 19, 4074−4077
Letter
Organic Letters Scheme 3. Cu-Catalyzed Triarylmethane Synthesisa,b
the reactions to proceed with high efficiency and chemoselectivity, although such groups may be redundant in the product structure. Gratifyingly, the tert-butyl groups on 8 could be efficiently removed partially or completely to yield 10 or 11 by following a reported procedure (Scheme 4c).11l For both Ag- and Cu-catalyzed reactions, the 1,6-addition product 3a was observed as a common intermediate (Scheme 5). Scheme 5. Preliminary Mechanistic Study
In either case, however, the proposed key intermediate 4a was not observed, which is believed to be highly reactive, and therefore undergoes the following steps spontaneously. We envisioned that the chemoselectivity between the formation of tricyclic ketal and triarylmethane is independent of the 1,6addition step, as the stereoselectivity of 3a will be lost upon deprotonation in the following step. To probe this, 3a was isolated in a pure form as a mixture of diastereomers (1.4:1 dr) and subjected to the standard Ag or Cu conditions. As expected, the desired products 6a or 8a were obtained with the same level of chemo- and stereoselectivity (Scheme 5). In conclusion, we have developed an effective catalyst-enabled divergent cascade reaction of activated isocyanides with paraquinone methide-aryl esters to produce skeletally diverse tricyclic ketals and triarylmethanes in excellent chemoselectivity. Current efforts in our laboratory are focused on the understanding of the origin of this chemoselectivity as well as the preparation of other types of products from this reaction.
a,b
See Table 1. cCarried out for 48 h. dIn this case, 8l and the corresponding tricyclic ketal were obtained in a ratio of 14:1.
triarylmethanes in uniformly excellent chemoselectivity and efficiency (>98% yield for 8a−8h). Different ester substituents on 1 were all suitable to produce 8i and 8j in excellent yields with excellent selectivities. Isocyanoacetates possessing different ester groups could also be used to produce 8k and 8l in good to excellent yields and selectivities. The high efficiency of this process, coupled with the operational simplicity (use of inexpensive Cu(OAc)2 and dppp as catalysts and running reactions open to air), makes it an attractive method for triarylmethane synthesis. To test the robustness and efficiency of our method in preparative synthesis, gram-scale reactions of 1f and 2a were carried out under the standard conditions (Scheme 4a). To our
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ASSOCIATED CONTENT
* Supporting Information S
Scheme 4. Large-Scale Reaction and Derivatization
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01851. Experimental details and characterization data (PDF) Crystallographic data for 6a (CIF), 6o (CIF), and 9 (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Yu Zhao: 0000-0002-2944-1315 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for the financial support from the Ministry of Education (MOE) of Singapore (R-143-000-613-112) and A*STAR SERC (R-143-000-648-305).
delight, the desired products 6f and 8f were obtained with no loss of efficiency or selectivity. Moreover, cleavage of the carbonate moiety in triarylmethane 8i took place smoothly by the treatment with potassium carbonate to generate bisphenol 9 in 84% yield (Scheme 4b). The structure of 9 was unambiguously determined by single crystal X-ray analysis. It is worth mentioning that the bulky tert-butyl substituents in the substrates were necessary for
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