In addition to all the professors who have been influential in my time at Caltech, my colleagues in the Stoltz lab have been a great help to me. Second, I want to thank all the collaborators I had, both before my time (Yuji Sumii, Katsuaki Baba and Hirokazu Takada) and during my time (Yanhui Lu and Austin Wright). I will always be grateful for all the love my family has given me.
PUBLISHED CONTENT AND CONTRIBUTIONS
L.G. participated in project design and manuscript preparation
LIST OF SCHEMES
LIST OF TABLES
Ray Crystallography Reports Relevant to Chapter 4
LIST OF ABBREVIATIONS
INTRODUCTION
While stereogenic C–F moieties have previously been studied, the compatibility of fluoroalkyl groups in palladium-catalyzed asymmetric allylic alkylation has remained unknown until recently. Due to our interest in the area of asymmetric allylic alkylation, we endeavored to build on these previous reports and investigate a series of fluoroalkyl and fluoroallyl derivatives in asymmetric allylic alkylation reactions. Herein, we report the first general method for the construction of carbo- and heterocyclic carbonyl derivatives bearing α-fluoro, α-fluoroalkyl, or α-(2-fluoro)allyl substituents using palladium-catalyzed enantioselective decarboxylative allylic alkylation (Scheme 11. .1D).
SYNTHESIS OF FLUORINATED ALLYLIC ALKYLATION SUBSTRATES SUBSTRATES
Synthesis of Fluorinated β-Ketoesters
- INITIAL REACTION OPTIMIZATION
- EXPLORATION OF REACTION SCOPE
- CONCLUSIONS
- EXPERIMENTAL METHODS AND ANALYTICAL DATA .1 MATERIALS AND METHODS .1 MATERIALS AND METHODS
The mixture was stirred vigorously at room temperature for 2 h, during which time the dark orange-brown color faded to yellow. After stirring at room temperature for 15 min, the mixture was cooled to 0 °C and a solution of trifluoromethyl reagent (561 mg, 1.65 mmol, 1.5 equiv) in acetonitrile (11 mL) was added dropwise at the same temperature. After stirring the reaction mixture at the same temperature for 24 hours, it was cooled to room temperature and quenched with an aqueous NH4Cl solution.
Representative Procedure 1: Enantioselective Allylic Alkylation
Representative Procedure 2: Racemic Allylic Alkylation
Representative Procedure 3: Racemic Allylic Alkylation
Representative Procedure 4: Preparatory Scale Reaction
METHODS FOR THE DETERMINATION OF ENANTIOMERIC EXCESS EXCESS
NOTES & REFERENCES
11 Absolute configuration of 5c was determined by comparison of the optical rotation of the same compound with the known literature value, see: Nakamura, M.; Hajra, A.; Endo, K.; Nakamura, E. 13 A defluorinated by-product was obtained in the presence of Pd(PPh3)4 for the preparation of racemic standards. Therefore, racemic samples were prepared in the presence of Pd2(dba)3 (or Pd2(pmdba)3) and achiral Gly-PHOX for fluoro-allyl products.
Palladium-catalyzed enantioselective Csp3-Csp3 cross-coupling for the synthesis of (poly)fluorinated chiral building blocks.
INTRODUCTION
Great progress has been made in the synthesis of proline derivatives, as shown by the prevalence of this motif in pharmaceutical compounds. Indeed, the synthesis of chiral proline derivatives was described in a review by Cativiela,3 an example of which is highlighted in Scheme 2.1.1 from the seminal work of Seebach et al.4 Starting from proline 20, condensation gives oxazolidinone 25, which can undergo enolate formation followed by alkylation resulting in 26. Hydrolysis of the resulting oxazolidinone then gives the proline derivative 27 in good yield and high ee.
Although this method is successful for the synthesis of a number of interesting molecules, it is limited to the synthesis of proline derivatives. Moreover, deprotection of the oxazolidonone may require harsh conditions, which may not be amenable to all substrates.
Synthesis of tetrasubstituted proline derivatives by Seebach et al. 4
Proposed synthesis of chiral 2,2-disubstituted pyrrolidines
- SYNTHESIS OF CHIRAL BENZYLOXYIMIDES
A year later, we demonstrated the decarboxylative asymmetric allylic alkylation reaction of cyclic β-keto esters, yielding the same α-quaternary ketone products (Scheme 2.2.1C). Since those initial reports, we have significantly expanded the scope of this reaction to include different ring sizes and heterocycles, especially following our development of an electron-deficient PHOX ligand (7).8 Of particular interest is progress on nitrogen heterocyles, including both lactams and imides, in the decarboxylative allylic alkylation reaction.9 We were pleased to find that a variety of β-amido esters were tolerated in this reaction, with only minor changes in reaction conditions (Scheme 2.2.1D). We believed that we could use some of these products as intermediates for the synthesis of chiral 2,2-disubstituted pyrrolidines in a catalytically asymmetric manner.
Progression of the asymmetric allylic alkylation reaction in the Stoltz laboratory
In addition to higher material throughput, the use of commercially available allyl chloroformate is superior to the use of allyl cyanoformate. The latter must be prepared from allyl chloroformate and involves the use of cyanide, requiring more complex treatment and waste disposal procedures. We were able to use the conditions optimized for the synthesis of 28a to access a number of β-amidoesters for the asymmetric allylic alkylation reaction as shown in Scheme 2.2.2C.
Synthesis of β-amidoesters
- REDUCTION OF BENZYLOXY IMIDE TO HYDROXAMIC ACID
So we continued our investigation with these two changes (Entry 3),11 and were pleased to see that the yield and selectivity remained the same. Increasing the concentration to 0.1 M resulted in a slightly accelerated reaction with similar selectivity and yield (entry 4), but increasing the concentration further resulted in lower yields and selectivities (entry 5–6). Reducing the catalyst loading even further (entry 7-9) resulted in similar selectivity and reactivity, although longer reaction times and higher temperatures were required.
Thus, we decided that the best overall combination of reactivity and catalyst loading was achieved in entry 7. With these optimized conditions, we turned to explore the reactivity of other substrates, one of which had never before been explored in an asymmetric allylic alkylation reaction. We were again pleased to observe good reactivity and selectivity for the parent substrate 29a on a larger scale, up to 11 g of substrate (Table 2.2.2).
Although somewhat disappointing, we were able to show that both of those substrates could be synthesized in good enantiomeric excess when the previously reported conditions were applied to both substrates for 5m (Entry B).12 With all four of our desired compounds in hand. , we turned our attention to advancing the compounds to chiral pyrrolidines. We were pleased to discover that a three-step sequence of reactions provided the desired hydroxamic acids 30a–d (Scheme 2.3.1). A subsequent dehydroxylation afforded lactams 35a–d in near quantitative yield upon treatment with a mixture of triethylsilane and trifluoroacetic acid (TFA).
Finally, the protected hydroxamic acids underwent debenzylation with boron trichloride to give the free hydroxamic acids 30a–d .
Synthesis of chiral hydroxamic acids
- THERMAL RING CONTRACTION OF HYDROXAMIC ACID
To test the ring contraction response, a number of functional group manipulations were necessary. First, selective carbonyl reduction proceeded in good yield in the presence of DIBAL-H, yielding alcohols 34a–d as a mixture of diastereomers. This series of reactions was highly scalable and was performed on scales up to 6 g on substrate 29a (R=Me).
These reactions are proposed to occur via an isocyanate-like intermediate in a manner similar to that proposed for the Hofmann rearrangement (Scheme 2.4.1d).5 Since the Hofmann rearrangement is known to proceed in a stereospecific manner, we predicted that the Spino reaction would also exhibit the same specificity, and we were ready to address this fundamental question. With our enriched lactams at 30 a-d and Spino's attempt at ring contraction of lactams in mind, we proceeded to investigate the stereospecificity of that ring contraction for the synthesis of 2,2-disubstituted asymmetric pyrrolidines.
Ring contraction reactions as reported by Spino et al. 5
Thermal ring contraction of chiral hydroxamic acid
- REACTIONS OF HYDROXAMIC ACID PRODUCTS
While we were indeed able to isolate pyrrolidine 37 as an HCl salt, we felt that the harsh conditions required were not ideal for more functionalized substrates, and the necessity of microwave irradiation proved to be a bottleneck when it was applied on larger scales. Returning to the proposed mechanism of the reaction, we were reminded that methyl carbamate was formed due to the methanol solvent, and decided to investigate the use of benzyl or tert-butyl alcohol as a solvent. We were pleased to discover that by using a 3:1 mixture of toluene and the desired alcohol we could synthesize both the Cbz- and Boc-protected pyrrolidines (Table 2.4.2, 31b and 31c respectively) in good yield, when there were slightly longer reaction times. applied.
Furthermore, we were able to use these conditions to access Cbz-protected pyrrolidines 31d-f in good to moderate yields from the corresponding hydroxamic acid precursors. Upon completion of the synthesis of these compounds, we continued to investigate our hypothesis that this reaction proceeds with stereoretention. Our development of the synthesis of Cbz-protected pyrrolidines proved to significantly accelerate this process, as we could use supercritical fluid chromatography (SFC) to determine the enantiomeric excess of pyrrolidine 31b .
We began by synthesizing the racemic allylic alkylation product 29a and progressing it to pyrrolidine 31b via the synthetic sequence described herein. The same sequence was then followed again, except using the enantioenriched allylic alkylation product 29a (92% ee, Scheme 2.4.3B). We were pleased to note that the pyrrolidine product 31b obtained from enantioenriched 29a retained the same enantiomeric excess (92% ee).
With this new method for the synthesis of chiral pyrrolidines, we attempted to apply our new strategy to the synthesis of the natural product.
Retrosynthetic analysis of tylohirsuticine
N–alkylation of chiral pyrrolidine
- CONCLUSIONS
- EXPERIMENTAL METHODS AND ANALYTICAL DATA .1 MATERIALS AND METHODS .1 MATERIALS AND METHODS
- Benzyloxyamine hydrochloride (10.30 g, 64.57 mmol, 1.1 equiv) in a 500 mL round-
Furthermore, we demonstrated that one of these substrates can be further developed to form a new indolizidine compound, which we hope to further develop into the natural product tylohirsuticine in the future. Reactions requiring external heat were modulated to the specified temperatures using an IKAmag temperature controller. 19F NMR spectra were recorded on a Varian Inova 300 spectrometer (282 MHz) and are reported in absolute chemical shift terms according to IUPAC standard recommendations of CFCl3.
1H NMR data are reported as follows: chemical shift (δ ppm) (multiplication, coupling constant (Hz), integration). Multiples are reported as follows: s = single, d = double, t = triple, m = multiple, br s = broad single, app t = apparently triple. Infrared (IR) spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and are reported in absorption frequency (cm-1).
A water condenser was attached and the reaction mixture was heated to gentle reflux (oil bath, 85 °C) for 12 h. The reaction mixture was diluted with EtOAc (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. The reaction mixture was diluted with 50 mL EtOAc, filtered over Celite and concentrated under reduced pressure.
The reaction mixture was then cooled, concentrated and purified by flash column chromatography (SiO 2 , 20% EtOAc in hexanes) to afford imide 29a as a pale yellow oil (182 mg, 88% yield, 92% ee).
Gram Scale Reaction
The reaction mixture was then cooled, concentrated, and purified by flash column chromatography (SiO2, 20% EtOAc in hexanes) to give imide 29c as a white solid (311 mg, 89% yield, 86% ee). The reaction mixture was then cooled, concentrated and purified by flash column chromatography, the mixture was then cooled, concentrated and purified by flash column chromatography (SiO2, 20% EtOAc in hexanes) to give imides 5m (307 mg, 80% yield, 84 % ee). The resulting two layers were separated and the aqueous phase was extracted with CH2Cl2 (3.0 mL × 1).
The combined organic layers were washed with brine (5.0 mL × 1), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the crude product. The residue was purified by silica gel flash column chromatography (SiO2, 15% EtOAc in hexanes) to.
