Thank you Brian, for all the time, effort and support you have given me in guiding me over the last five years. Thanks to Joe Drew, Agnes Tong, Alison Ross and all the CCE staff for maintaining the division. At Caltech, I met many members of the Stoltz group; there are dozens (by my count, at least 110 Stoltz members) that I have interacted with over the years.
The members of the Reisman, Fu, and Peters groups, who occupy the rest of the second and third floors of Schlinger (and the members of the Grubbs lab) were also great people interacting with and from learning. The many students, faculty, and administrators of the UCLA-Caltech Medical Scientist Training Program, and especially the entering class of 2012—thank you for your support and friendship. Much of the chemistry in this chemistry thesis would not have happened in the absence of the individuals mentioned above, as well as many others - thank you.
This thesis presents several projects that further expand the field of Pd-catalyzed decarboxylative allylic alkylation and examine its applications in the synthesis of medically important small molecules. Next, we explore the utility of gem-dissolved heterocycles in the context of medicinal chemistry.
INTRODUCTION AND BACKGROUND
Since this seminal development in asymmetric decarboxylative alkylation, many groups have made further contributions to extend this methodology to encompass a variety of acyclic and cyclic substrates. 8, 9 Table 1.1 below summarizes some of the many gem disubstituted cyclic products that our laboratory has synthesized using the DAAA reaction, highlighting the incredible versatility of this mild reaction.4,7,10–16. Then, in the attached two appendices, we describe the DAAA of five- and seven-membered diazaheterocycles.
PIPERAZINONE and TETRAHYDROPYRIMIDINONE DAAA
Other non-enantioselective methods to synthesize gem-disubstituted piperazines include [4+2] cycloadditions of 1,2 diamines with propargyl alcohols developed by Rawal (Scheme 1.2B),34 and the ring expansion of oxetane spirocycles by Carreira (Scheme 1.2C) . .43. Instead, we resorted to a low-yield 5-step convergent sequence starting at an amino acid (Scheme 1.3A). Presumably, the electron-withdrawing Boc group weakens the nucleophilicity of N4, allowing divergent access to a wider range of substrates 1.3 via enolate functionalization of dicarbonyl compound 1.2, which could be synthesized in just two steps from Boc-piperazinone 1.1 (Scheme 1.3B). .
Given that N-Boc piperazin-2-one substrates provide excellent results, we wondered whether a class of isomeric substrates, N-Boc tetrahydropyrimidin-2-ones (1.5), would also perform similarly (Scheme 1.4c). In 2018, the Shibasaki group described a decarboxylative allylic alkylation of the N,O heterocycle to set up a quaternary stereocenter, followed by heterolysis of the N–O bond to form β2,2-amino acids (Scheme 1.4a).47 Later in 2018, Cossy and co-workers described a similar approach, involving intermolecular allylic alkylation (Scheme 1.4b).48 Notably, the substrate scope for these two examples is limited to mostly α-benzyl and α-aryl compounds. If decarboxylative alkylation could be achieved with the versatile tetrahydropyrimidin-2-one framework, a wider range of chiral β2,2-amino acids could be accessible (Scheme 1.4c).
With LiOH, the benzoyl group can be orthogonally removed to provide the free amide 1.9 (Scheme 1.5b). In contrast, the carboxylic acid functional groups, chloroallyl, and pendant fluorine atoms of the new unprotected carboxylic acids, chloroallyl, and fluorine 1.14-16 can be directly obtained by reverse-phase preparative HPLC purification after the two-step deprotection sequence. steps (Scheme 1.5e).
Preparation of Known Compounds
Allyl cyanoformate was prepared according to the method of Weber.54 Phosphinoxazoline (PHOX) ligands (S)-L1, (S)-L2, and achiral GlyPhox were prepared by methods described in our previous work.4,55 Dibenzoylated allylic alkylation substrate 1.3g was prepared according to the method of Korch.15 Tris(4,4'-methoxydibenzylideneacetone)dipalladium(0) [Pd2(pmdba)3] was prepared according to the method of Ibers56 or Fairlamb.57 AgOPiv was prepared using Grubbs ' procedure.58 tert-Butyl ((phenylsulfonyl)methyl)carbamate and benzyl ((phenylsulfonyl)methyl)carbamate were prepared according to the method of Zwierzak or Dikshit.59,60 Benzyl 3-oxopiperazine-1-carboxylate was prepared according to the method of Batey.61 2-Chloroallyl chloroformate was prepared according to the method of Stoltz.62.
EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA
- Procedures for the Synthesis of Piperazinone Allylic Alkylation Substrates Substrates
- Procedures for the Synthesis of Tetrahydropyrimidinone Allylic Alkylation Substrates Alkylation Substrates
- General Procedure for Allylic Alkylation Optimization Screen Optimization of Reaction Parameters
- General Procedure for Pd-Catalyzed Decarboxylative Allylic Alkylation Reactions Alkylation Reactions
- Experimental Procedures and Spectroscopic data for the Pd- Catalyzed Decarboxylative Asymmetric Allylic Alkylation of Piperazinone Catalyzed Decarboxylative Asymmetric Allylic Alkylation of Piperazinone
- Experimental Procedures and Spectroscopic Data for the Pd- Catalyzed Decarboxylative Asymmetric Allylic Alkylation of Catalyzed Decarboxylative Asymmetric Allylic Alkylation of
- Experimental Procedure for the Gram Scale Decarboxylative Asymmetric Allylic Alkylation of Benzyl Tetrahydropyrimidinone 1.5e
- Experimental Procedures for the Transformations of Decarboxylative Allylic Alkylation Products Decarboxylative Allylic Alkylation Products
- Determination of Enantiomeric Excess
The combined organic layers were dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure on silica gel. The combined organic layers were dried over anhydrous Na 2 SO 4 , decanted and concentrated under reduced pressure on silica. The combined organic phases were dried over anhydrous Na2SO4, decanted and concentrated under reduced pressure on silica gel.
The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure on silica gel. The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure on silica gel. The reaction mixture was diluted with EtOAc (10 mL) and allowed to warm to room temperature.
The aqueous phase was extracted with EtOAc (3 x 15 mL) and the combined organic phases were dried over anhydrous Na2SO4, decanted and concentrated under reduced pressure on silica gel. The reaction mixture was stirred at 0 °C for 3 h and diluted with saturated aqueous NH4Cl (2 mL) and EtOAc (2 mL). The aqueous phase was extracted with EtOAc (4 x 3 mL) and the combined organic phases were dried over anhydrous Na2SO4, decanted and concentrated under reduced pressure on silica gel.
The aqueous phase was extracted with EtOAc (3 x 3 mL) and the combined organic phases were dried over anhydrous Na 2 SO 4 , decanted and concentrated under reduced pressure on silica gel. The combined organic phases were dried over anhydrous Na 2 SO 4 , decanted and concentrated under reduced pressure. The reaction mixture was allowed to warm to room temperature, stirred for 3 hours and concentrated under reduced pressure.
The reaction mixture was stirred for 1 h, diluted with EtOAc (2 mL) and washed with saturated aqueous NaHCO 3 . The aqueous phase was extracted with EtOAc (3x3 mL) and the combined organic phases were washed with brine (3 mL), dried over anhydrous Na2SO4, decanted, and concentrated under reduced pressure on silica gel. The solution was extracted with EtOAc (3x5 mL), dried over Na2SO4, decanted and concentrated under reduced pressure.
The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The reaction was stirred at room temperature for 1 hour and then acidified with 1 M HCl (4 mL).
Enantioselective synthesis of α-quaternary Mannich adducts by palladium-catalyzed allylic alkylation: Total synthesis of (+)-sibirinine. Catalytic Enantioselective Synthesis of Acyclic Quaternary Centers: Palladium-Catalyzed Decarboxylative Allylic Alkylation of Fully Substituted Acyclic Enol Carbonates.
