I would also like to thank Matt Hesse for his constant support and willingness to talk about chemistry. Finally, I would like to thank Eric Welin for his constant wisdom and seemingly endless knowledge of chemistry and sports. I have to thank Katerina Korch for working with me to review the chapters in the book, and also for being one of the nicest people I know.
Specifically, I would like to thank again everyone I mentioned above, as well as David Schuman, Tyler Fulton, Nick Hafeman, Fa Ngamnithiporn, Austin Wright, Dr. I want to thank the entire Caltech staff for all their help and assistance over the years, especially Dr. I would also like to thank Mike Takase and Larry Henling for their assistance in obtaining the X-ray diffraction data, as well as Drs.
I would also like to thank Rick Gerhart and Jeff Groseth for their excellent work in the glass and electronics shops. I have to thank my mother, Annette, and late father, Victor, for being such wonderful parents.
Enolate Types and Their Formation
- Alkali and Alkaline Earth Metal Enolates
- Silyl Enol Ethers
- Boron Enolates
- Transition Metal Enolates
Aldol Reaction
- Introduction
- Rhodium-Catalyzed Reactions
- Palladium-, Platinum-, and Nickel-Catalyzed Reactions
- Scandium- and Neodymium-Catalyzed Reactions
- Reactions Proceeding Through Boron Enolates
Mannich Reaction
- Introduction
- Copper-Catalyzed Reactions
- Palladium-Catalyzed Reactions
- Scandium-Catalyzed Reactions
- Nickel-Catalyzed Reactions
- Lithium-Catalyzed Reactions
- Calcium-Catalyzed Reactions
Conjugate Addition and Michael Reaction
- Michael Additions Involving Potassium Enolates
- Michael Additions Involving Cobalt Enolate
- Michael Additions Involving Nickel Enolates
- Michael Additions Involving Copper Enolates
- Michael Additions Involving Europium Enolates
- Michael Additions Involving Rhodium Enolates
- Michael Additions Using Lanthanum–BINOL Complexes
- Michael Additions Involving Platinum and Iron Enolates
- Michael Additions Involving Palladium Enolates
- Michael Additions Involving Scandium and Yttrium Enolates
- Michael Additions Involving Calcium Enolates
- Conjugate Addition Reactions Involving Manganese Enolates
Allylic Alkylation
- Introduction
- Palladium-Catalyzed Asymmetric Allylic Alkylations of
- Molybdenum-Catalyzed Asymmetric Allylic Alkylations
- Iridium-Catalyzed Allylic Alkylations
- Rhodium-Catalyzed Allylic Alkylations
- Nickel-Catalyzed Allylic Alkylations
Miscellaneous Alkylations
- Asymmetric Alkylations of Chromium Enolates
- Asymmetric Alkylations of Lithium Enolates
- Introduction
- Palladium-Catalyzed Reactions
- Nickel-Catalyzed Reactions
- Copper-Catalyzed Reactions
Pericyclic Reactions
- Claisen-Type Reactions
- Conia-Ene Reactions
Notes and References
Initial Reaction Optimization
Exploration of Reaction Scope
Adapting the Low Catalyst Loading Allylic Alkylation
Conclusion
Experimental Methods and Analytical Data
- Materials and Methods
- Experimental Procedures
- Methods for the Determination of Enantiomeric Excess
- Notes and References
Retrosynthetic Analysis
Synthesis of Cross-Coupling Fragments
Cross-Coupling and Elaboration to the Carbocyclic Core
Chemical Oxidation of Desoxy-Nigelladine A
Enzymatic Oxidation of Desoxy-Nigelladine A
Conclusion
Experimental Methods and Analytical Data
- Materials and Methods
- Protocols for Protein Expression and Lysis
- Experimental Procedures
- Enzymatic Screens and Enantiomer Screen
- Chemical Oxidation Tables
- Comparison of Natural and Synthetic Nigelladine A
- Notes and References
Ray Crystallography Reports Relevant to Chapter 3
Retrosynthetic Analysis; Transannular Diels–Alder
Synthesis of Convergent Coupling Fragments
Fragment Coupling and Ring Closing Metathesis
Retrosynthetic Analysis; Oxidative Enolate Coupling
Second Generation Synthesis of the Cyclopentene Diol Fragment
Alkyne Synthesis and Fragment Coupling
Intramolecular Diels–Alder Reaction and Late-Stage Functionalization
Third Generation Retrosynthetic Analysis; Ring Expansion
Synthesis of [2+2] Precursor
Future Directions
Conclusion
Experimental Methods and Analytical Data
- Material and Methods
- Experimental Procedures
- Notes and References
Ray Crystallography Reports Relevant to Chapter 4
Their proposed mechanism for the reaction proceeds via enolization of a substituted b-ketoester (35 and 36) to form a chiral palladium enolate, which reacts with a highly electrophilic aldehyde in a selective manner to produce products containing a chiral quaternary center (37 and 38). ) with good yield (up to 92% yield) and enantioselectivity (up to 80% ee, Scheme 1.3.3.1). Moderate to good yields (40 to 90%) were obtained for almost all products containing quaternary carbon, with diastereoselectivities greater than 20:1 and enantioselectivities above 92%. The diastereoselectivity of the reaction was excellent, ranging from 93:7 to 98:2 with preferential formation of diastereomer 81 .
In 1991, Botteghi, Boga and co-workers reported the asymmetric Michael reaction using cobalt catalysts derived from a variety of ligand architectures (Scheme For the formation of the quaternary carbonaceous product, the optimal ligand was found to be a tetradentate diaminodiol ligand 91. use of tridentate ligands in coordination with nickel centers in the asymmetric Michael reaction has been investigated by Christoffers and co-workers, instead Christoffers and co-workers have reported mild conditions using nickel diamine complexes for the asymmetric Michael reaction of cyclic b-ketoesters and methyl vinyl ketone.60 The enantioselectivity of the reaction was very depending on the ring size of the cyclic b-ketoester; the cyclohexanone-derived product could be obtained in 91% ee, but the cycloheptanone-derived product was almost racemic with an ee of only 2% (Table 1.5.3.1) ).
Scettri and colleagues reported in 199364 an early example of the Michael reaction of a 1,3-dicarbonyl compound and methyl vinyl ketone to produce various quaternary carbonaceous products, using the commercially available europium(III)tris(3-trifluoromethylhydroxymethylene-d -camphorate)) as a catalyst under very mild conditions. Temperature played a major role in the enantioselectivity of the reaction, with the best enantioselectivities (up to 73% .ee) being obtained at 0 °C. The enantioselectivity of the reaction was good for some substrates with ee's up to 86%.
Williams and co-workers have reported the use of platinum catalysts in the asymmetric Michael reaction. Although the reaction proceeded in near-quantitative yield, the product was completely racemic due to the conformational flexibility of the halide-abstracted catalyst. The diastereoselectivity of the reaction was also good with dr's ranging from 5:1 to greater than 30:1.
Initial p-coordination of the allyl group with Pd generates complex (163), which subsequently allows oxidative insertion of the ester bond to the Pd(II) complex (164). Stoltz and colleagues also found that use of the more electron-deficient (CF3)3-t-Bu-PHOX (168) gave excellent yields and enantioselectivities with benzoyl-protected lactam substrates (e.g. 169) and also with strained cyclobutanones (e.g. 166) (Schemes. Representative products of the palladium-catalyzed asymmetric allylic alkylation reaction developed by Stoltz and co-workers.
Ethyl, isopropyl, and t -butyl ester substituents were also well tolerated, although the extent of reactivity with respect to the a substituent in the b -ketoester was not examined. Previous work with this reagent revealed that the use of triethylamine as a base in toluene resulted in the formation of (Z)-boron enolate.161 Corey applied this method to the synthesis of (+)-b-elemene (283). Homologation of the carbon chain leading to the terminal alkyne was not tolerated in the reaction, and products bearing six- or seven-membered rings could not be generated.
Addition of silver trifluoroacetate or silver triflate boosted the yields of these reactions; however, the enantioselectivity of the reaction remained unsatisfactory (Scheme 1.9.2.4).
Alkali metal bases are one of the most common reagents used to form kinetic enolates. In a subsequent publication, the substrate scope of this reaction was investigated and it was found that substrate architecture played an enormous role in the selectivity of the reaction.54 The highest enantioselectivity obtained in the substrate scope study was only 39%, what was the result for the reaction of cyclohexanone-derived b-ketoester with acrolein at 20 °C. It was concluded that minor modifications in the ligand structure would not be enough to significantly improve the enantioselectivity of the reaction and alternative routes would have to be explored to obtain better results.
The use of chiral alkali metal base catalysts in the asymmetric Michael reaction to form quaternary centers extends beyond Shibasaki's work. The use of palladium pincer complexes in the asymmetric Michael reaction was further explored by Uozumi and co-workers in 2004.84 They also investigated the asymmetric Michael reaction of vinyl ketones (108) and α-cyanocarboxylates (28), but. In 1998, the first asymmetric α-arylation reaction of ketone enolates giving quaternary stereocenter-containing products was reported by Buchwald and co-workers.139 Using 10–20 mol% of a palladium(0)-(R)-BINAP complex catalyst in toluene at elevated temperatures, 2-methyl-α-tetralone (220) could be α-arylated with a variety of aryl bromides, affording modest to good yields (40-74%) and enantioselectivities (61-88% ee) of the quaternary stereocenter -containing products 224 (table 1.8.2.1).
The scope of the reaction was quite broad, yielding α-vinyl derivatives of 2-alkylcyclopentanones, 2-methylcyclohexanone, 2-methyl-α-tetralone (229), and 2-methyl-1-indanone (230) all in good condition. to excellent yields (76–96%) and modest to good enantioselectivities (50–92%). Although both reactions yielded a product of 85% ee at 80°C, the reaction of the aryl triflate was faster, allowing this reaction to be performed at a lower temperature. The first was reported in 1995 by Corey and co-workers.160 Their enantioselective rearrangement between Ireland and Claisen relies on the use of chiral boron reagent 283, which provides good control over the geometry of the intervening boron enolate.
Another example of the use of cooperative catalysis in the asymmetric Conia-ene reaction of malonic ester amide 311 comes from Kumagai, Shibasaki and co-workers.174 Their initial catalyst system involved the combination of La(NO3)3, an amide-based chiral ligand used. 313, and the protonated amino acid ester H-l-Val-Ot-Bu, in 1:1:3 ratio, in the presence of a mild Lewis acid.
