development and applications of the palladium-catalyzed

First, I must thank Professor Brian Stoltz, who has been a great advisor, mentor, and friend. His feedback on my research and proposals has been invaluable, and I have enjoyed our interactions during my time here. She has been a great support to me while writing my thesis, spending many days at the Broad typing.

Introduction to Enantioselective Oxidation Chemistry

Oxidation in Biological Systems

Enantioselective Oxidations in Synthetic Chemistry

Oxygenase-Type Reactions
Oxidase-Type Reactions

Oxidative Kinetic Resolution of Alcohols

Kinetic Resolutions
Previous Catalytic Enantioselective Alcohol Oxidations
Subsequent Enantioselective Alcohol Oxidations

Conclusion

Notes and References

The Development of the Palladium-Catalyzed Oxidative Kinetic

Background and Introduction

Chiral alcohols are present in many natural products, pharmaceuticals, and useful synthetic materials and are extremely versatile as synthetic intermediates in the construction of other functional groups. Due to its prevalence in a number of enantioselective transformations7 and known utility in the aerobic oxidation of alcohols, we chose to pursue palladium(II) as a catalytic metal for the oxidative kinetic resolution of secondary alcohols.8,9 Particularly intriguing was a report by Uemura of racemic alcohol oxidation using a palladium(II) catalyst and pyridine in toluene (Scheme 2.1.1).10 Using molecular oxygen as the sole stoichiometric oxidant, high yields of aldehydes and ketones were obtained for a range of alcohols. We expected that the use of chiral ligands instead of pyridine would lead to significant enantiodiscrimination in the oxidation, while the ligand acceleration could minimize background racemic oxidation of other Pd(II) species that may be present in the reaction.

Reaction Development

Original Conditions
Rate Acceleration with Exogenous Base and a
Chloroform as Solvent in the Resolution

Notably, an acetate is coordinated to the palladium center throughout the catalytic cycle, indicating the possible importance of the Pd(II) counterion in solution. Pd(nbd)Cl2 proved to be the most effective precatalyst, giving good selectivity in the oxidation of a number of benzyl alcohols (Scheme 2.2.1). The reactivity of this complex was significantly diminished relative to the complex generated in situ with a 4:1 sparteine:Pd loading (Table 2.2.2).15a.

We have demonstrated that monodentate amines do not generate catalytically active systems for alcohol oxidation with Pd(nbd)Cl2 (Table 2.2.4).10b While (–)-sparteine (28) promotes rapid alcohol oxidation (entry 3), little oxidation occurs with either pyridine (entry 1) or quinuclidine (entry 2). Sparteine (28), which is much more soluble in toluene, can act as a better kinetic base than the heterogeneous cesium carbonate for the neutralization of hydrogen chloride generated in the formation of the palladium alkoxide (Scheme 2.2.2). The inclusion of tert-butyl alcohol proved to be an excellent exogenous alcohol addition, providing more active catalytic systems for alcohol oxidation.25 We optimized the process to maintain high selectivity over a range of secondary alcohols while dramatically shortening reaction times ( Table 2.2.5, cf entries 1 and 2).

We investigated the addition of various tert-butoxide salts to these resolutions (Table 2.2.6, entries 2-4). Spectroscopic evidence for the formation of hydrogen bonds between chloroform and catalytic species was found in IR spectra of CDCl3 solutions (Table 2.2.8).34 A significant shift in the C-D stretching frequency of CDCl3 occurred in the presence of (–)- sparteine (28, item 2) or Pd(sparteine)Cl2 (66, item 3).35,36 The observed decrease in λmax corresponds to a lower energy CD stretch frequency due to a weaker C-D bond relative to free CDCl3 when species that accept hydrogen bonds are present. As shown in Table 2.2.9, a 1:1 ratio of chloroform and toluene (entry 2) performs as well as pure chloroform (entry 1) as a solvent.

Carrying out the reactions at 23 °C gives a dramatic increase in catalyst selectivity (cf. Table 2.2.10, point 1 and Table 2.2.5).

Figure 2.2.1 Stuctures of ligands in Table 2.2.1.

Conclusion

Experimental Section

Materials and Methods
General Oxidative Kinetic Resolution Conditions
Screening and Optimization Studies
Methods for Determination of Conversion
Methods for Determination of Enantiomeric Excess

Initial dissolution conditions in PhCH3 without Achiral Base.14 To an oven-dried reaction tube with a stir bar was added 3Å molecular sieves (250 mg). The tube was then heated to 80 °C with vigorous stirring under an O2 atmosphere (1 atm, balloon) for 20 min. Aliquots were filtered through a small plug of silica gel (Et2O eluent), evaporated and analyzed by GC for conversion and chiral HPLC for alcohol ee.

Accelerated resolution conditions in PhCH3 under O2.18 3Å molecular sieves (250 mg) were added to an oven-dried reaction tube with a stir bar. CHCl3 Conditions with O2.28 3Å molecular sieves (250 mg) were added to an oven-dried reaction tube with a stir bar. The reaction was allowed to warm to 23 °C and stirred vigorously under an O2 atmosphere (1 atm, balloon) for 15 min.

CHCl3 conditions with ambient air.28 To an oven-dried reaction tube with stir bar, 3A molecular sieves (250 mg) were added. Aliquots were filtered through a small plug of silica gel (Et2O eluent), evaporated and analyzed by GC for conversion to acetophenone (26). All conversions were determined by GC (Table 2.4.1) against the internal standard (tridecane), unless otherwise indicated in the text.

Table 2.4.1 Methods for determination of conversion.

Notes and References

A significant effect of cesium carbonate structure and particle size was found for palladium-catalyzed aryl halide aminations in toluene consistent with a heterogeneous process, see: Meyers, C.; Maes, B. 23) Addition of sparteine•HCl inhibits alcohol oxidation, see ref. 13a. For a discussion of chloroform hydrogen bonding and its effect on IR vibrational frequencies, see: Green, R. 36) The chloroform molecule is also within hydrogen bonding distance in the solid structure of the dichloride complex 66.

Background and Introduction

A broad survey of secondary alcohols was undertaken to evaluate the generality of the conditions for oxidation and successful resolution. Furthermore, these studies were intended to test the developed selectivity models of the catalyst.6 Finally, substrate scope exploration would demonstrate the utility of the process, leading to practical applications.

Substrate Scope of the Palladium-Catalyzed Enantioselective Oxidation

Benzylic Alcohols
Allylic Alcohols
Cyclopropylcarbinyl Alcohols
General Trends and Limitations
Selectivity Model

The widespread use of chiral allylic alcohols in organic synthesis led to an investigation of this important class of molecules in the following. The resolution of acyclic allylic alcohols has proved more challenging, although Eric Ferreira and Jeffrey Bagdanoff, graduate students in these laboratories, found that allylic alcohol 104 could be obtained with good selectivity at 23 °C in chloroform (entries 31 and 32). The successful resolution of benzylic alcohols prompted an exploration of aryl substituents on cyclic allylic alcohols.

These substrates are readily prepared via Suzuki coupling of arylboronate esters and iodoenones9 followed by Luche reduction (Scheme 3.2.1).10 Satisfactorily, subjecting these alcohols to any of our developed kinetic resolution conditions yields highly enriched allylic alcohols. with enantio (Table 4). .11 Electron-rich (entries 9–12) and electron-poor (entries 17–19) 2-aryl substituents lead to excellent selectivities. Again, allylic alcohols with 2-aryl substituents are oxidized rapidly and with extremely high selectivity (entries 1–8). Interestingly, analogous allylic 2-alkyl alcohols unsubstituted in the 3-position are oxidized with poor selectivity (cf. Table 3.2.5, entries 9–16 and Table 3.2.3, entries 2–4 and 14).

The presence of vicinal heteroatoms (e.g. (±)-133 and (±)-134) hinders the oxidation, presumably through catalyst coordination and deactivation.12 Finally, unactivated alcohols (e.g. (±)-135 and (±)-136 ) , especially primary alcohols, are slow to oxidize under any of our developed conditions.13. Theoretical calculations of the oxidative kinetic resolution by the Goddard group14 and X-ray crystallographic analysis of a number of palladium complexes by Raissa Trend, a graduate student in these laboratories,6 led to a better understanding of the main factors involved in determining the preference of the catalyst for oxidation of one enantiomer of alcohol over the other. Key to high selectivity is a substrate-counterion interaction in the transition state for β-hydride elimination (Scheme 3.2.2).

Complex 141 can proceed through a β-hydride elimination transition state ( 142 ) by shifting the coordinated chloride ion to the apical position of the complex to subsequently generate the product ketone 143 .

Table 3.2.1 Resolution of 1-arylethanols.

Applications

meso-Diol Desymmetrizations
Kinetic Resolution / Claisen Sequence
Resolution of Pharmaceutical Intermediates
Resolution of Intermediates in Natural Product Syntheses

To further demonstrate the utility of the palladium-catalyzed enantioselective alcohol oxidation, Jeffrey Bagdanoff investigated several meso-diol arrays. To further highlight the utility of the enantioselective alcohol oxidation, the conversion of dissolved alcohols into other synthetically useful building blocks was investigated. Although the yield for this vinylation process is modest, the rest of the mass balance is predominantly recovered allyl alcohol.

Modification of the protocol, including the use of stoichiometric Hg(OAc)2 and changes in reaction temperature and time, did not improve the yields. The Claisen rearrangement of vinyl ether 159 to form a quaternary carbon center also proceeds in good yield and high enantiomeric excess. The widespread use of enantio-enriched alcohols in synthesis offers numerous applications for kinetic resolution.

A number of alcohols that have been successfully resolved are intermediates in the synthesis of a variety of pharmaceuticals (Scheme Daniel Caspi, a graduate student in these laboratories, has Boc-protected γ-amino alcohol (–)-89 and bromoarene (–) -87 successfully resolved enantiomeric excess with good corresponding selectivity Aminoalcohol (–)-89 can be converted into an intermediate in the synthesis of a number of antidepressants, including fluoxetine•HCl (Prozac, 171).21 Bromoarene (–)-87 can is converted into a known intermediate in the synthesis of the leukotriene receptor antagonist montelukast sodium (Singulair, 172).22 Finally, allylic alcohol (–)-121, resolved with an outstanding s factor of 83, is an intermediate in the enantioselective synthesis of hNK-1 receptor antagonist 173.23 The palladium-catalyzed oxidative kinetic resolution has also been applied to the construction of enantioenriched secondary alcohols in the context of natural product total synthesis.

The highly enantio-enriched indole (–)-178 has been further developed into the first enantioselective total synthesis of the ergot alkaloid (–)-aurantioclavine.

Table 3.3.1 Claisen rearrangement of allylic alcohols.

Conclusion

Finally, meso -diol 182 undergoes palladium-catalyzed oxidative desymmetrization to directly afford the alkaloid (–)-lobeline, which is a nicotinic acetylcholine receptor antagonist.

Experimental Section

General Oxidative Kinetic Resolution Conditions
Preparative Procedures

The reaction was quenched by the addition of crushed ice (10 g) and then saturated aqueous NH 4 Cl (20 mL). The reaction was then quenched by slow addition of saturated aqueous NH 4 Cl (20 mL) and H 2 O (10 mL). The reaction mixture was diluted with 4:1 hexanes:EtOAc (2 mL) and allowed to stir vigorously for 20 min to precipitate white solid.

After the reaction mixture was allowed to warm to 23°C, the solvent was removed under reduced pressure. Once the reaction was complete, as determined by TLC, it was filtered through Celite (140 mL EtOAc eluent). The reaction was pressurized with carbon monoxide (100 psi) and heated to 80°C behind a blast shield for 21 hours.

After cooling to 23 °C and venting the carbon monoxide, the reaction mixture was diluted with Et 2 O (70 mL) and filtered through a short plug of Celite (Et 2 O eluent). Prepared by the method according to Charette.59 The characterization data matched the data in the literature.60 [α]D. Prepared by the method of Charette.59 The characterization data matched the data in the literature.

Prepared by Charette's method.63 The characterization data were consistent with the data in the literature.64 [α]D. The reaction mixture was allowed to warm to 23 °C and stir for 2 h, after which it was quenched with excess Na2SO4•10H2O. The reaction was cooled to 23 °C, filtered through a short plug of silica gel (eluent EtOAc), and concentrated under reduced pressure to afford tetrahydrofuran 170 (21.0 mg, 85% yield) as a colorless oil.

Notes and References

For examples of bidirectional synthesis/terminus differentiation in natural product synthesis, see: (a) Harada, T.; Kagamihara, Y.; Tanaka, S.; Sakamoto, K.;.

Spectra Relevant to Chapter 3