Letter Cite This: Org. Lett. 2018, 20, 1248−1251
pubs.acs.org/OrgLett
Palladium-Catalyzed Asymmetric Nitrogen-Selective Addition Reaction of Indoles to Alkoxyallenes Seok Hyeon Jang,†,∥ Hyun Woo Kim,‡,∥ Wook Jeong,† Dohyun Moon,ζ and Young Ho Rhee*,† †
Department of Chemistry, Pohang University of Science and Technology, 77 Cheongam-Ro, Nam-Gu, Pohang, Gyeongbuk 37673, Republic of Korea ‡ Center for Molecular Modeling and Simulation, Korea Research Institute of Chemical Technology, 141 Gajeongro, Yuseong-Gu, Daejeon 34114, Republic of Korea ζ Beamline Department, Pohang Accelerator Laboratory, 80 Jigokro-127-beongil, Nam-gu, Pohang, Gyeongbuk 37673, Republic of Korea S Supporting Information *
ABSTRACT: A new palladium-catalyzed asymmetric addition reaction of indoles to alkoxyallenes is reported. Remarkably, the reaction showed complete regioselectivity toward the nitrogen. A new mechanism distinct from that of conventional π-allyl chemistry is proposed to explain this unique selectivity. The utility of the reaction is demonstrated by highly efficient and flexible synthesis of N-glycosylindoles.
I
tions for the indole synthesis.6 Thus, direct N-substitution reaction of indole free of competing C-substitution represents a significant synthetic challenge. Herein, we report our recent results on the Pd-catalyzed asymmetric addition reaction of indole to alkoxyallene. Remarkably, this reaction showed complete regioselectivity for nitrogen regardless of the electronic properties of indoles, although the reaction shares π-allyl metal complex as the common intermediate with the allylic substitution reaction. Calculation studies established a new mechanism for C−N bond formation of indole promoted by the coordination of the indole anion to the σ-allyl Pd complex. From a synthetic viewpoint, this reaction gives a highly efficient access to indole N-glycosides when combined with a metal-catalyzed ringclosing-metathesis (RCM) reaction. Indole glycosides such as ribofuranosyl indoles7 and neosidomycin8 have received considerable attention because of their unique biological activities. Because of the low nucleophilicity of indole nitrogen, synthesis of this type of compound in many cases relies on the indirect method using more reactive indoline nucleophile and the subsequent dehydrogenation. In addition, the ligand-driven stereoselectivity may be useful for the synthesis of 2deoxyindole glycosides such as K-252a and other staurosporine natural products which exhibit unique activities.9 Initial studies for the enantioselective N-addition reactions were guided by our previous work10,11 on the palladiumcatalyzed asymmetric addition reaction of heteroatom nucleophiles to alkoxyallenes and other related reports in this area.12−16 Based upon the pKa value of indole (pKa ∼21 in DMSO),17 we reasoned that indole may be a suitable
ndoles containing stereogenic C−N bonds are found in numerous bioactive compounds.1 Thus, the efficient asymmetric C−N bond formation of indole is of great importance in synthetic organic chemistry. Due to the high nucleophilicity of the C3 position of the indole, the C−N bond formation is complicated by competing C−C bond formation (Scheme 1).2 This issue has been well-addressed in the metalcatalyzed allylic substitution reaction of indole mediated by the π-allyl metal species. In most cases, the scope of the Nsubstitution is limited to indoles bearing electron-withdrawing groups.3 Other indirect methods using indoline4 or hydrazine nucleophiles5 require additional functional group transformaScheme 1. Mechanistic Issue and Application
Received: January 18, 2018 Published: February 5, 2018 © 2018 American Chemical Society
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DOI: 10.1021/acs.orglett.8b00191 Org. Lett. 2018, 20, 1248−1251
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Organic Letters nucleophile for the addition reaction. Indeed, a preliminary reaction of unsubstituted indole using achiral dppp ligand with readily available alkoxyallene 1 at room temperature in toluene generated the racemic adduct 2 in 73% yield (entry 1, Table 1).
Table 2. Scope of Indole Substrates with Allene 1
Table 1. Optimization of Reaction Conditions
entry
ligand
time (h)
solvent
yielda (%)
eeb
1 2 3 4 5
dppp (R,R)-L1 (R,R)-L1 (R,R)-L1 (R,R)-L2
21 5 4 26 26
toluene toluene CH2Cl2 1,4-dioxane toluene
73 93 94 80 trace
98 90 99
entry
R
timea (h)
product
yieldb (%)
eec
1 2 3 4 5 6 7d 8 9
5-Br 5-OMe 4-F 4-NO2 3-CO2Me 7-CO2Me 2-CO2Et 2-Ph 2,3-trimethylene
2.5 6.5 3 3 3 72 23 23 21
5 6 7 8 9 10 11 12 13
98 91 87 92 94 70 93 82 74
98 96 97 85 93 >99 98 95 98
a Reaction time for the first step. bIsolated yield. cMeasured after the RCM reaction. d5 mol % of Pd2(dba)3/10 mol % of L1 was used.
Scheme 2. Stereodivergent Cyclic Glycoside Synthesis
a Isolated yield of the acyclic product 2. bThe ee value of 3 after the ring-closing metathesis reaction.
Remarkably, no competing C3-allylation was observed. The subsequent RCM reaction using catalyst 4 (5 mol %) provided the cyclic product 3 in near-quantitative yield. As described in entry 2, asymmetric version of the addition reaction was successfully accomplished when the ligand L1 (5 mol %) was used with Pd2(dba)3 (2.5 mol %). The following RCM reaction produced enantioenriched 2 in 98% ee (entry 2). Using CH2Cl2 solvent for the indole addition somewhat lowered the ee of 2 (entry 3), while employing dioxane showed poorer conversion (entry 4). The use of ligand L1 proved critical because switching to L2 nearly stopped the conversion of Pd-catalyzed reaction (entry 5). The absolute stereochemistry of the stereogenic carbon was tentatively assigned to be (S) at this point, based upon the analogy to our previous works. (For a detailed procedure for the structural confirmation, see below.) Notably, the asymmetric reaction led to the enantioselection opposite that reported for the hydrocarbanation of alkoxyallene using the same type of ligand.12c With the optimized conditions in hand (entry 2, Table 1), we examined the scope of indoles in the reaction with alkoxyallene 1. As depicted in Table 2, a wide range of indoles bearing substituents at the 3-, 4-, and 5-positions participated well in the reaction to give the dihydropyranylated products in high yield and ee, regardless of the electronic nature of the substituent (entries 1−5). Again, excellent regioselectivity was observed. Interestingly, placing an ester group at the 7-position of indole had significantly slowed the reaction; the product was obtained in 70% yield after 72 h (entry 6). Introduction of substituents at the 2-position worked reasonably well to produce the desired compounds in terms of the yield and the enantioselectivity (entries 7−9). Next, we tested chiral ene− alkoxyallene (compounds 14 and 15) to investigate the liganddriven diastereoselectivity.18 As depicted in Scheme 2, the use of these bulkier alkoxyallenes had no particular adverse effects on the conversion and the stereoselectivity. Both α- and βforms of indole glycosides could be accessed with comparable efficiency by simply varying the chiral information on the ligand. Using these conditions, the synthesis of pyranosylated
(compounds 16−20) as well as the furanosylated product (compound 21) were successfully accomplished. The excellent chemoselectivity is noted by the reaction of tryptophan, which led to the formation of 22 in comparable yield and ee to other examples. Finally, the reaction of more densely substituted allene 15 also proceed smoothly to give 23 in a stereodivergent manner. To address the synthetic utility of the reaction, we examined the Os-catalyzed stereoselective dihydroxylation of some products obtained in Scheme 2. As depicted in Scheme 3, complete stereoselectivity was observed for both pyranosylated and furanosylated indoles, demonstrating that the stereoselectivity of this reaction was effectively controlled by the indole moiety. Thus, the key fragments of various bioactive compounds shown in Figure 1 can be easily accessed by sequential metal (Pd−Ru−Os) catalysis. X-ray crystallographic analysis confirmed the structure of compound 24a, which 1249
DOI: 10.1021/acs.orglett.8b00191 Org. Lett. 2018, 20, 1248−1251
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Organic Letters
various N-glycosyl indole derivatives. Currently, we are working on expanding the scope of the addition reaction based upon the new mechanism.
Scheme 3. Acetal-Directed Dihydroxylation
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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.8b00191. Experimental data and 1H and 13C spectra for all new compounds (PDF) Computational details and structural information (PDF) Accession Codes
CCDC 1575251 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID Figure 1. Energy profile and the mechanism.
Young Ho Rhee: 0000-0002-2094-4426 Author Contributions ∥
verifies the stereochemical assignments of the Pd-catalyzed asymmetric addition. (For the structural assignment of compound 24a, see the Supporting Information.) From a mechanistic viewpoint, the unique regioselectivity observed in this study reasonably excludes conventional mechanism14 invoking outer-sphere addition of nucleophile (indole anion) to the π-allyl metal complex. DFT calculations using an achiral system shed more light on the mechanism on the substitution. As depicted in Figure 1, π-allyl complex A19 is in fast equilibrium with σ-ally isomers B and C wherein indole anion is coordinating to the Pd.20−22 In addition, a new lowenergy pathway was located (solid line in Figure 1), which involves the addition of the indole anion to the allylic carbon in the σ-ally complex B to form the product D. Most notably, the competing C3-addition leading to E from B has a significantly higher barrier (by 4.9 kcal/mol) than the desired N1-addition. An alternative pathway leading to D via the reductive elimination of isomeric σ-allyl complex C seems to be an unlikely process according to the calculation, due to the extremely high energy of the transition state.23 Thus, the computational study verifies a catalytic cycle high-lighting coordination-assisted substitution via the formation of σ-allyl complex depicted in Figure 1. This mechanism and energy profile are consistent with the regioselectivity observed in the current work. (For more information on the calculation data, see the Supporting Information.) In summary, we developed a new Pd-catalyzed asymmetric N-selective addition reaction of indole to alkoxyallene. A wide range of indoles participated well in the reaction, generating Nglycosides in high yield and regioselectivity. The current work for the first time clarifies the mechanism of asymmetric heteroatom addition to alkoxyallene. Moreover, we demonstrated the utility of this reaction by the facile synthesis of
S.H.J. and H.W.K. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support for this work was provided by the National Research Foundation of Korea, which is funded by the Korean Government (NRF-2015R1A2A1A15056116). X-ray crystallography at the PLS-II 2D-SMC beamline was supported in part by MIST and POSTECH.
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