Abstract
Aryl and alkenyl amino acid derivatives were synthesized by a palladium catalyzed 1,4 addition of the corresponding boronic acids to 2-acetamidoacrylate.
Our laboratory is interested in developing small molecule inhibitors of protein-protein interactions. Recent studies showed that the tetrapeptide pSPTF binds the carboxy terminus domains of the early onset breast cancer gene 1 (BRCT-BRCA1) with micromolar affinities.1 Structural studies show that the phenylalanine residue (F) in pSPTF makes a key hydrophobic contact with the BRCT-BRCA1.2 To explore this hydrophobic pocket we planned to generate unnatural amino acids with various aryl side chain.
Metal catalyzed 1,4 addition of organometallic reagents to acetamidoacrylates is an effective strategy to access unnatural amino acids and rhodium has been the metal of choice to carry out this transformation.3 Recently a palladium phosphite system was successfully used in the 1,4 addition of arylboronic acids to generate 3-arylpropanoic acid derivatives.4 The phosphite in the palladium catalyzed 1,4 addition, suppressed the typically observed Mizoroki-Heck type of oxidative coupling product.
We speculated that palladium phosphite catalyzed 1,4 addition of aryl boronic acid to 2-acetamidoacrylate could provide a direct route to aryl and alkenyl side chain containing unnatural amino acids. In this communication, we report the synthesis of various aryl and alkenyl amino acid derivatives generated by a palladium-phosphite catalyzed 1,4-addition of the corresponding boronic acids to acetamidoacrylate. Our studies show palladium (low cost option) can serve as a viable alternative to rhodium for the synthesis of unnatural amino acids from acetamidoacrylates.
In the previously reported palladium-phosphite catalyzed 1,4-addition of arylboronic acids to eneones, the formation of the desired product and two side products, viz., biaryl formed due to the oxidative homocoupling and the Mizoroki-Heck product was reported.4b Our initial attempts to add a rather bulky boronic acid (10-bromoanthrace-9-ylboronic acid) to methyl-2-acetamidoacrylate using the reported palladium-phosphite catalyzed 1,4 addition conditions failed to produce either the desired or the side products. Therefore we carried out a survey of bases and solvents to identify the optimal conditions for the reaction (summarized in Table 1).
Table 1.
Optimization of the palladium-phosphite catalyzed 1,4-addition of arylboronic acid to methyl-2-acetamidoacrylate
 | |||||
|---|---|---|---|---|---|
| % Isolated yield | |||||
| Entrya | Base | Solvent | 3 | 4 | 5 |
| 1 | NaOAc | DMF | 0 | 15 | 20 |
| 2 | CsF | DMF | 25 | 30 | 0 |
| 3 | Na2CO3 | DMF | 50 | 13 | 0 |
| 4 | Cs2CO3 | DMF | 59 | 13 | 0 |
| 5b | Cs2CO3 | DMF | 0 | 25 | 40 |
| 6 | Cs2CO3 | DMSO | 59 | 12 | 0 |
| 7 | Cs2CO3 | Toluene | 0 | 9 | 10 |
| 8 | Cs2CO3 | THF | 52 | 12 | 0 |
| 9 | Cs2CO3 | DCM | 0 | 30 | 0 |
Reaction conditions: Pd(OAc)2 (0.06 mmol), P(OPh)3 (0.05 mmol), 1 (1.3 mmol) and 2 (1.0 mmol)
Pd(OAc)2 (1 mmol)
Unlike the addition to enones, we found that the use of carbonates (entry 3 and 4, Table 1) as the base yielded the highest amounts of the desired product, while the use of sodium acetate (entry 1, Table 1) resulted in the formation of the oxidative Mizoroki-Heck product. We also found that the use of polar aprotic solvents resulted in higher yields of the desired product when compared to non-polar solvents. Additionally, under catalytic conditions the reaction did not go to completion and with stoichiometric amount of Pd(OAc)2 the major product isolated was the Mizoraki-Heck product (entry 4 vs entry 5, Table 1). A plausible mechanistic pathway for this observation shown in Scheme 1, is identical to that of the corresponding addition to enones.4 The insertion of the arylpalladium species into the acetamidoacrylate leads to two possible intermediates A and B that are probably in equillibrium.5 The desired product is generated when the palladium enolate A is quenched while the β-hydride elimination of B will yield the Mizoroki-Heck product. The presence of excess acetate (either by the addition of sodium acetate or the use of stoichiometric amounts of palladium acetate) drives the equilibrium towards B resulting in the formation of the unsaturated product 5.
Scheme 1.
Plausible mechanism
We extended this methodology (entry 4, Table 1) to generate a set of unnatural amino acids (summarized in Table 2).6a We obtained the desired products in modest yields (50–60%) and in most cases isolated the oxidatively homocoupled biaryl as the side product. Compounds 3a, 3b, 3c, 3d and 3f are known, while compounds 3e and 3g are new unnatural amino acids.6
Table 2.
Synthesis of unnatural amino acids via the palladium-phosphite catalyzed 1,4-addition of arylboronic acid to methyl-2-acetamidoacrylate
 | |||
|---|---|---|---|
| % Yield | |||
| Entry | Ar | 3 | 4 |
| a |  |
50 | 12 |
| b |  |
51 | 0 |
| c |  |
52 | 0 |
| d |  |
49 | 9 |
| e |  |
59 | 8 |
| f |  |
56 | 9 |
| g |  |
60 | 11 |
In summary, we report a palladium-phosphite catalyzed 1,4 addition of aryl or alkenyl boronic acids to generate unnatural amino acids. We are currently exploring the use of chiral phosphites in this reaction and will be reported in due course.
Acknowledgments
This work was supported by NIH R01CA127239.
Footnotes
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References
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