Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Ligand-Promoted γ‑C(sp3)−H Arylation and Unsymmetrical Diarylation to Access Unnatural Amino Acid Derivatives Suvankar Das,† Gurupada Bairy,†,‡ and Ranjan Jana*,†,‡ †
Organic and Medicinal Chemistry Division, CSIR-Indian Institute of Chemical Biology 4 Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, West Bengal, India ‡ Academy of Scientific and Innovative Research (AcSIR), Kolkata 700032, West Bengal, India S Supporting Information *
ABSTRACT: A palladium(II)-catalyzed arylation of a γC(sp3)−H bond of protected amino acid is explored. The monoarylation is promoted by the commercially available, inexpensive phenanthroline ligand, and toxic silver salt is replaced by earth-abundant Mn(III)acetate. Subsequently, a hitherto unknown unsymmetrical diarylation at the γ-position is accomplished under the modified reaction conditions. Ligands have a prominent influence in both mono- and unsymmetrical diarylations.
O
route for direct access to unnatural amino acids.4,6−8 Furthermore, this technique has tremendous potential for the late-stage functionalization of complex peptides, aptamers, and proteins for stapling to infer conformational rigidity and bioconjugation with other biomolecules.9−11 However, stereoselective C−H activation/functionalization of sp3 C−H bond is extremely challenging due to its inertness, ubiquitous presence, and lack of required trajectory due to its conformational flexibility. In past decades, an enormous effort was dedicated to the stereoselective synthesis of unnatural amino acids via sp3 C−H activation.9,12−15 However, these methods are mostly limited to the functionalization of accessible β-C−H bonds,12 which mainly proceeds through the formation of a favorable fivemembered palladacycle. In fact, functionalization of the remote γ-C−H bond through a C-terminus directing group is underdeveloped,13,14 presumably due to the formation of an energetically unfavorable six-membered palladacycle.9d As a consequence, most of the methodologies suffer from harsh reaction conditions, limited substrate scope, use of super stoichiometric silver salts, commercially unavailable expensive ligands, and directing groups, etc. To circumvent this, the γproximity of the metal center could be achieved by an Nterminus directing group through the formation of an energetically favorable five-membered palladacycle. We report herein a picolinamide-directed, palladium-catalyzed expeditious route for remote γ-arylation of natural and unnatural amino acids under silver-free conditions. For the first time, we have accomplished a ligand-enabled unsymmetrical diarylation at the sp3-hybridized γ-C−H bonds. Commercially available and inexpensive picolinamide (PA) is known to deliver a Pd(II) catalyst to a proximal γ-C−H bond through the formation of a favorable five-membered pallada-
wing to their better absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile, design and development of peptide-based drugs are emerging.1 While peptide-based drug discovery programs have heavily relied on natural peptides in the last decades,2 a paradigm shift toward nonproteinogenic amino acids has been witnessed in the drug discovery and delivery program (Figure 1).3 Typically, de novo
Figure 1. Unnatural amino acid containing drugs.
synthesis of amino acids focused on enantioselective bond construction across the Cα center, which requires expensive chiral ligands and a special laboratory setup.4 Alternatively, existing α-amino acid (αAA) precursors are diversified via synthetic manipulations of side chains (e.g., serine and aspartic acid).4,5 Complementary to these conventional strategies, selective functionalization of side chain C−H bonds, particularly sp3-hybridized C−H bonds of various readily available αAA precursors, may provide a viable and practical © XXXX American Chemical Society
Received: March 17, 2018
A
DOI: 10.1021/acs.orglett.8b00874 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters cycle.13,16 Therefore, we chose PA-protected valine methyl ester (1a) as a model substrate to optimize the reaction conditions for γ-arylation (Table 1). When 1a was treated with
4-iodoanisole (2a) in the presence of 10 mol % of Pd(OAc)2 and 2 equiv of AgOAc at 120 °C under neat conditions, 32% monoarylated product (3a) along with 23% diarylated product (4a) was isolated (for details, see Table S1 in the Supporting Information, SI). The introduction of bases, additives, and solvents increased the overall yield to some extent, but the ratio of 3a and 4a remained unaltered, forcing us further to identify a suitable oxidant and ligand, which may play a crucial role in controlling the ratio of 3a and 4a as well as in increasing the rate of conversion. Pyridine-based monodentate ligands (L1− L6, Scheme 1) and N−P ligands (L7 and L8, Scheme 1) were found to be inefficient for this transformation. However, some improvement in the ratio of 3a and 4a was observed when bidentate N,N-ligands (L9−L11, Scheme 1) were introduced. To our delight, a dramatic improvement was observed when commercially available, “conformationally restricted” bidentate 1,10-phenanthroline (L12) was introduced and silver(I) carbonate was replaced by environmentally benign Mn(III)acetate dihydrate as oxidant, furnishing 75% overall yield in a 5:2 ratio of 3a and 4a (Scheme 1). With the optimized reaction condition in hand, we evaluated the scope for aryl iodides for the arylation of PA-protected Lvaline methyl ester (1a). Aryl iodides bearing both electrondonating and electron-withdrawing groups were compatible under these reaction conditions, providing moderate to good yields (Table 2). Methoxy-, keto-, nitro-, and trifluoromethylsubstituted aryl iodides furnished good yield (entries 1−3 and 9, Table 2), whereas aryl iodides containing ester, cyano, and halogen groups and heteroaryl iodide (2-iodothiophene) provided moderate yields of the corresponding products (entries 4 and 6−11, Table 2). The monoarylation products
Table 1. Optimization of the Reaction Conditiona
entry
deviation from standard condition
yield (%) (3a/4a)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Ag2CO3 instead of Mn(OAc)3·2H2O under oxygen environment under nitrogen environment 0.5 equiv of Mn(OAc)3·2H2O used KHCO3 (4 equiv) added as additive NaHCO3 (4 equiv) added as additive 10 mol % of Pd(OAc)2 used 1 equiv of K2CO3 added instead of 3 equiv without Pd(OAc)2 KF (1 equiv) added as additive without K2CO3 Na(HCO)3 and CsF used standard condition 30 mol % of ligand used
58 (38/20) 74 (51/23) 63 (42/21) 46 (31/15) 62 (37/25) 72 (43/29) 69 (47/22) 68 (44/24) NR 60 (43/17) 14 (14/00) 44 (30/14) 75 (52/23) 49 (40:9)
a
All reactions were carried out at 0.1 mmol scale. bYields are overall isolated yields, and the product distribution was measured from NMR.
Scheme 1. Ligand Optimization for γ-C(sp3)−H Arylationa,b
a
All reactions were carried out at 0.1 mmol scale. bYields are overall isolated yields, and the product distribution was measured from NMR. Pd(TFA)2 was used instead of Pd(OAc)2, and Ag2CO3 was used instead of Mn(OAc)3·2H2O, with TFA added. dPd(OAc)2, 15 mol % instead of 10 mol %; NaHCO3 was used instead of K2CO3 and CsF added, under O2 environment.
c
B
DOI: 10.1021/acs.orglett.8b00874 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
rich aryl iodides were found to be more reactive in comparison to electron-deficient aryl iodides. Heteroaryl iodides such as 2iodothiophene and 5-iodo-N,N-dimethyl uracil also provided moderate yield for corresponding arylation products (3y,z, Scheme 2). We were delighted to obtain a single diastereomer for the expected products (3t−3z), which indicates that the diastereoselectivity is controlled by the steric factor initiated by enhanced chain length at the γ-C center. Although ligand-enabled unsymmetrical diarylation of amino acids at the β-position was reported,12b to the best of our knowledge, unsymmetrical diarylation of amino acids at the remote γ-position is unknown. Thus, our next aim was to explore sequential γ-C(sp3)−H arylation of monoarylated amino acid derivatives (3) to afford unsymmetrical diarylation products (5). Unfortunately, our initial attempt for the second arylation of the previously formed monoarylated product 3a under the same reaction condition was in vain. Thus, we were prompted to identify suitable conditions and ligands for this unsymmetrical diarylation. During ligand optimization for monoarylation, we observed that although most of the ligands provided monoarylation as a major product, the selectivity was reversed with electron-rich, linear L20, which furnished diarylation as a major product (Scheme 1). Keeping this in mind, when monoarylated product 3a was subjected to the reaction conditions with L20 in lieu of 1,10-phenanthroline, the expected diarylation product was isolated in 57% yield. Interestingly, very high diastereoselectivity (>20:1) of the diarylation product was observed (5a, Scheme 3). Next, we proceeded to explore the substrate scope for this novel unsymmetrical γ-diarylation of amino acid. When monoarylation products were subjected to the reaction conditions, diarylation products (5a−5j, Scheme 3) were obtained in good to moderate yields. Notably, 3b and 3d bearing an electron-deficient aryl counterpart provided relatively higher yield for the corresponding unsymmetrical diarylation products. Simple iodobenzene provided good yields when reacted with compound 3. Gratifyingly, 5-iodo-N,Ndimethyl uracil also provided moderate yield, which expanded the scope for heteroaryl iodides in this methodology (5j, Scheme 3). The diastereoselectivity of the unsymmetrical γdiarylation products remains unaltered from their corresponding starting monoarylation products. Notably, the reaction of 1a with bromobenzene provided 33% of the corresponding γ-arylation product, but chlorobenzene remains unreactive under the reaction conditions. The exact mechanism of manganese-promoted, Pd-catalyzed γ-C−H arylation is unclear at this moment. In the literature, γC−H arylation under a PdII/AgI catalytic system is proposed to proceed via a PdII/PdIV catalytic cycle.13a,b,16 In this present PdII/MnIII catalytic system, the oxidative addition of PdII to aryl iodide may take place via either a two-electron or a singleelectron transfer mechanism. When the standard reaction was performed with 1 equiv of TEMPO, the yield of the γ-arylation product was decreased drastically and was completely diminished with 2 equiv of TEMPO. This result indicates that there is a possibility of oxidative addition to aryl iodide through a single-electron transfer pathway to generate intermediate III, as depicted in Scheme 4. Further, we synthesized intermediate II (Scheme 4) by following the reported literature16b and continued the reaction between intermediate II and aryl iodide (2a) under various reaction conditions. It was observed that, in the absence of Mn(III), a very trace amount of the desired product was formed. In the
Table 2. Substrate Scope of Aryliodide with PA-L-ValOMea,b
entry
R
products (3/4)
1 2 3 4 5 6 7 8 9 10 11
4-OMe-C6H4 4-COCH3-C6H4 4-NO2-C6H4 4-CO2Et-C6H4 2-OMe-C6H4 2-CO2Me-C6H4 4-CN-C6H4 4-Cl-C6H4 4-CF3-C6H4 2,4-F2-C6H3 2-thiophene
3a/4a 3b/4b 3c/4c 3d/4d 3e/4e 3f/4f 3g/4g 3h 3i 3j 3k
% yield (3/4) 74 68 70 62 61 56 61 54 66 33 48
(52/22) (50/18) (51/19) (47/15) (34/27) (40/16) (51/10) (54/0) (66/0) (33/0) (40/8)
dr for 3c 5:1 7:1 6:1 8:1 10:1 5:1 6:1 11:1 10:1 5:1 5:1
a
All reactions were carried out in 0.2 mmol scale. bYields refer to the average of isolated yields of at least two experiments. cDiastereoselectivity was determined by 1H NMR.
(3) were separated as an inseparable mixture of two diastereoisomers by column chromatography. Among those, o-methoxy-, chloro-, trifluoromethyl-, and p-carboxyethylestersubstituted aryl iodides afforded high diastereoselectivity of the monoarylation products (3d,e, 3h,i; Table 2). Gratifyingly, pchloro-, p-trifluoromethyl-, 2,4-difluoro-substituted aryl iodides afforded monoarylation products (3h−3j; Table 2) exclusively, and no diarylation products were obtained. Further, we explored the scope for other amino acids containing γ-C(sp3)−H bonds such as D-2-aminobutyric acid and L-isoleucine. The corresponding PA-protected methyl esters 1b and 1c offered good to moderate yield (3l−3z, Scheme 2). Notably, unsubstituted iodobenzene and electronScheme 2. Substrate Scope of Amino Acidsa,b
a
All reactions were carried out at 0.2 mmol scale. bYields refer to the average of isolated yields of at least two experiments. cDiastereoisomeric ratio >20:1. dTrace amount of diarylation product was isolated. C
DOI: 10.1021/acs.orglett.8b00874 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters Scheme 3. Substrate Scope of Unsymmetrical Diarylationa,b,c
a
All reactions were carried out in 0.2 mmol scale. bYields refer to the average of isolated yields of at least two experiments. cDiastereoisomeric ratio >20:1.
Finally, the directing group was removed by heating the final product with BF3·Et2O in ethanol at 140 °C for 30 h. A representative example is shown in Scheme 5.
Scheme 4. Plausible Mechanistic Pathway
Scheme 5. Removal of the Directing Group
In conclusion, we have developed a ligand-enabled, practical methodology for remote γ-C(sp3)−H bond arylation. Commercially available, inexpensive 2-picolinic acid is used as a directing group, and earth-abundant manganese(III)acetate is used in this palladium(II) catalysis to replace toxic silver salt. Moreover, extremely challenging unsymmetrical diarylation at the γ-C(sp3)−H bonds has also been demonstrated for the first time.
absence of L12, compound 4 was isolated as a major product along with a trace amount of 3. However, formation of compounds 3 and 4 in a ratio of 2:1 was observed in the presence of 2 equiv of L12 and 1 equiv of Mn(III) with respect to intermediate II, indicating their requirement in this methodology (for details, see the SI). After reductive elimination from intermediate III, the γ-arylation product and a PdII or PdI species are generated. The PdI species might be oxidized to PdII by Mn(III)/areal oxygen. However, this observation is too preliminary to predict the exact mechanism and warrants further studies. Furthermore, Mn(OAc)3 may readily disproportionate to generate Mn(II) and Mn(IV) and subsequently oxidize to more Lewis acidic Mn3O(OAc)7 that increases the electrophilicity of the PdII species to facilitate the C−H insertion step.12j It may also serve as an acetate shuttle in the catalytic cycle.
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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.8b00874. Experimental procedures, spectroscopic data, 1H and 13C NMR spectra for all synthesized compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. D
DOI: 10.1021/acs.orglett.8b00874 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters ORCID
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Ranjan Jana: 0000-0002-5473-0258 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was financially supported by DST, SERB, Govt. of India via Ramanujan fellowship (Award No. SR/S2/RJN-97/ 2012 and Extra Mural Research Grant No. EMR/2014/ 000469), and SERB National Postdoctoral fellowship (Fellowship Reference No. PDF/2016/000828) to S.D.; and G.B. thanks UGC, Govt of India for his fellowship.
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DOI: 10.1021/acs.orglett.8b00874 Org. Lett. XXXX, XXX, XXX−XXX
