I really enjoyed my rotation in the Robb group during my first semester of graduate school. I have had the privilege of collaborating with quite a few talented people on a selection of projects in the Stoltz group. I also had the opportunity to work with Alex on allylic alkylation of diazaheterocycles when I started in the group as a graduate student.
Mentoring Jonathan in the lab was a very enjoyable experience, and I'm glad that of all the projects he could have worked on, he chose this one. I am grateful to have worked with and learned from each of these project partners and look forward to seeing the great things they will do in the future. I would like to thank Alex Cusumano, with whom I worked in the Spalding cellar during the COVID-19 pandemic.
It is very motivating to be able to talk to such interesting and smart people every day in the lab. In the summer of 2019, I had the opportunity to serve as a mentor to Liz Park, an undergraduate WAVE fellow.
Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 1,4-
Diazepanes are common structural motifs found in a variety of drugs (Figure 1.2.1), including the benzodiazepine anxiolytics,8 the antipsychotic clozapine9 and the anti-insomnia drug suvorexant.10 Notably, many of these compounds lack Csp3 complexity. The lack of stereochemically complex diazepanes in the pharmaceutical landscape, especially those bearing quaternary stereocenters with only carbon, is likely due to a lack of asymmetric methods for their synthesis, leading to a reliance on kinetic resolution, either of a quaternary building block or of the diazepane itself. 11 The efficient and enantioselective incorporation of gem disubstitution into diazepane heterocycles could enable the development of pharmaceuticals with improved properties due to the unprecedented advantages of increasing saturation in drug molecules.5,6 Furthermore, increased substitution on the diazepane. ring could potentially block metabolically labile sites and thus improve the pharmacokinetic profile of a drug candidate. Subsequent functionalization of 18a–c was performed with a variety of electrophiles, yielding substrates 19a–1 bearing different functional groups.
In previous research by our laboratory, 2:1 hexanes/toluene proved to be an effective solvent system for achieving high ee with a variety of lactam substrates.3e Indeed, compound 20a was obtained in 87% ee under these conditions (entry 6 ). While investigating reaction conditions, we also discovered that the use of the highly electron-deficient ligand (S)-Ty-PHOX13 resulted in reduced ee (entry 8). First, the effect of the electronics of the lactam protecting group on the reaction outcome was investigated.
It is worth noting that the use of a p -anizoyl protecting group was not beneficial for enantioselectivity in all cases ( 20a / 20e , 20f / 20g ) and was often equal to the unsubstituted benzoyl group. The low yield of propargyl lactam 20i and the need for elevated reaction temperatures are also noteworthy—allylic alkylation of other α-propargyl lactams studied by our group proceeded smoothly.3e It is possible that the geometry of the diazepanone substrate favors coordination of the alkyne to the palladium, which hinders the desired reactivity.
Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 4-
A synthetic route to unsubstituted imidazolidinone 30 was published in 1988 by Pinza and co-workers (Scheme 1.3.2).17 Glycinamide hydrochloride (26) was subjected to benzylation by reductive amination with benzaldehyde to obtain secondary amine 27. After replicating Pinza's synthesis of 4-imidazolidinone, we aimed to derivatize this compound and prepare substrates for Pd-catalyzed decarboxylative asymmetric allylic alkylation (Scheme 1.3.3). Although this pathway suffered from excessive length and inconsistency, access to 33 nonetheless allowed us to begin evaluating the Pd-catalyzed decarboxylative asymmetric allylic alkylation of 4-imidazolidinone substrates.
We were aware of a synthetic route to imidazolidinones that relied on the Beckmann rearrangement of 3-azetidinones (Scheme 1.3.6A) and hoped to use this strategy to prepare 1-Boc-4-imidazolidinone 31, expanding our existing synthetic route would intercept. Nitta and co-workers prepared O-tosyloxime 38 in 2 steps from carbamate 36 and found that this oxime derivative underwent facile Beckmann rearrangement when simply passed through a column of neutral or basic alumina, yielding imidazolidinone 39.18 Analogous oxime 41 was facile available via commercially available 3-azetidinone 40 in 2 steps (Scheme 1.3.6B), but in our hands a column of basic alumina could not affect the rearrangement after tosylation. Pinza later reported that Witkop's reaction was difficult to reproduce and had a consistently low yield.17 However, being aware of the success of nickel boride-promoted reductive desulfurization of other cyclic thiourea,24 including aryl-substituted imidazolidinones,25 work began we are developing an improved route. to 4-imidazolidinones from thiohydantoins (Scheme 1.3.12).
The new synthetic route depicted in Scheme 1.3.12 generates key intermediate 33 in 25% overall yield over only 4 steps. Having demonstrated the broad functional group tolerance of the reported method, we sought to investigate the feasibility of further functionalization of the 4-imidazolidinone products (Scheme 1.3.13).
Conclusion
Despite extensive experimentation, the highest yielding conditions identified for the conversion of imidazolidinone 35a to amino ester 54 (H2SO4/MeOH) gave highly variable results, with the maximum observed yield of 54 being only 25%.
Experimental Section
- Materials and Methods
- Experimental Procedures
- General Procedure for Allylic Alkylation of Diazepanones
- Synthesis of Diazepanone Allylic Alkylation Substrates
- Derivatization of Diazepane Allylic Alkylation Products
- General Procedure for Allylic Alkylation of Imidazolidinones
- Synthesis of Imidazolidinone Allylic Alkylation Substrates
- Derivatization of Imidazolidinone Allylic Alkylation Products
- Determination of Enantiomeric Excess
After complete consumption of the starting material, as monitored by TLC, the reaction mixture was exposed to air. The crude reaction mixture was loaded directly onto a flash column and the product was isolated by silica gel flash chromatography. The reaction mixture was then poured into saturated aqueous NH 4 Cl (20 mL), the layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 mL).
The reaction mixture was then poured into saturated aqueous NH 4 Cl (30 mL), the layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 mL). After stirring for 3 hours at -78°C, the reaction mixture was poured into saturated aqueous NH4Cl (10 ml) and extracted with ethyl acetate (3 x 20 ml). After stirring for a further 45 minutes at 53°C, the reaction mixture was cooled to 23°C and poured into saturated aqueous NH4Cl (25 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). ).
After stirring for 8 hours, the reaction mixture was allowed to cool to 23°C and poured into saturated aqueous NH 4 Cl (5 mL), the layers were separated and the aqueous phase was extracted with ethyl acetate (3 x 2 mL). The reaction mixture was heated to 50°C and stirred for 19 hours, leaving starting material as judged by TLC. After stirring for 15 minutes at 0°C, anhydrous MgSO 4 was added and the mixture was stirred for a further 10 minutes, after which it was filtered through celite and concentrated under reduced pressure.
After stirring for an additional 1 hour at 23 °C, the reaction mixture was quenched with saturated aqueous NaHCO3 (3 mL), the layers were separated and the aqueous layer was extracted with CH2Cl2 (3 x 2 mL). The crude reaction mixture was loaded directly onto a flash column and the product was isolated by silica gel flash chromatography (10%). After the NaBH4 addition was complete, the reaction mixture was removed from the ice bath and allowed to warm to 23 °C.
After stirring for an additional 13 minutes, the reaction mixture was poured into 1 N aqueous HCl (200 mL) and extracted with ethyl acetate (3 x 50 mL). After stirring for an additional 10 minutes, the reaction mixture was poured into 1 N aqueous HCl (20 mL) and extracted with ethyl acetate (4 x 15 mL). The reaction mixture was warmed to 0 °C and stirred for 45 min, resulting in a light yellow solution.
Then NH4Cl (3 ml) was added and the resulting mixture was stirred vigorously for 30 minutes. The reaction vessel was sealed and the reaction mixture was stirred in a heating block at 70°C for 3 days.
Reaction mechanism, origin of enantioselectivity and reactivity trends in asymmetric allylic alkylation: A comprehensive quantum mechanical study of a C(sp3)-C(sp3) cross-coupling. Direct Reductive Cyclocondensation of the Nitro Group with the Amido Group: Key Role of the Iminophosphorane Intermediate in the Synthesis of 1,4-Dibenzodiazepine Derivatives. Addition of chiral glycine, methionine and vinylglycine enolate derivatives to aldehydes and ketones in the preparation of enantiomerically pure α-amino-β-hydroxy acids.
Transition metal-free in situ generation of terminal alkenes: synthesis of multisubstituted acrylamidines via tandem sp3 C–H olefination/sp2 C–H arylation reactions. Thiohydantoins: Selective N- and S- Functionalization for Liebeskind-Srogl Reaction Study Synthesis Recent reviews: a) Vogt, H.; Bräse, S. Recent approaches to the asymmetric synthesis of α,α-disubstituted α-amino acids. b) Bera, K.; Namboothiri, I. N. N. Asymmetric Synthesis of Quaternary α-Amino Acids and Their Phosphonate Analogues. Rapid synthesis of an electron-defective t-BuPHOX ligand: cross-coupling of aryl bromides with secondary phosphine oxides.
Boron trifluoride etherate-mediated O-acylation of ketone enolates with allyl 1H-imidazole-1-carboxylate - a convenient procedure for the synthesis of substituted allyl enol carbonates. Synergistic Cu/Pd catalysis for the enantioselective allylic alkylation of aldimine esters: access to α,α-disubstituted α-amino acids.
Attempts to Improve Bilane Synthesis
Unexpected Synthesis of a Monoazaporphyrin
Conclusion
Experimental Section
- Materials and Methods
- Experimental Procedures
Ray Crystallography Reports Relevant to Chapter 3
The research in the Stoltz group is primarily focused on the total synthesis of complex, bioactive natural products and on the development of reaction methods to enable these synthetic efforts. The majority of the content of this thesis focuses on permutations of this central goal.
