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Cite This: J. Am. Chem. Soc. 2018, 140, 14647−14654
Rhodium-Catalyzed Enantioconvergent Isomerization of Homoallylic and Bishomoallylic Secondary Alcohols Rui-Zhi Huang,† Kai Kiat Lau,† Zhaofeng Li,‡ Tang-Lin Liu,*,†,‡ and Yu Zhao*,† †
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Republic of Singapore 117543 School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, China
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J. Am. Chem. Soc. 2018.140:14647-14654. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 11/08/18. For personal use only.
S Supporting Information *
ABSTRACT: We present herein an unprecedented enantioselective isomerization of homoallylic and bishomoallylic secondary alcohols, catalyzed by a commercially available rhodium-complex and a base. This catalytic redox-neutral process provides an effective access to chiral ketones in high efficiency and enantioselectivity, without the use of any stoichiometric reagent or generation of any waste. For the reaction of homoallylic alcohols, this system achieved not only a stereoconvergent access to chiral ketones bearing a β-stereocenter (up to 95%, 86% ee) but also a concomitant oxidative kinetic resolution of the alcohol substrates (S > 20). In the case of bishomoallylic alcohols, an intriguing ligand-induced divergent reactivity was observed. A terminal-to-internal alkene isomerization promoted by Rh/L7 followed by redox isomerization using Rh/BINAP system produced chiral ketones bearing a γ-stereocenter with high yield and enantioselectivity. Mechanistic studies provided strong support for the redox-isomerization pathway with chain walking of the key alkyl-Rh intermediate.
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INTRODUCTION To achieve sustainable chemical synthesis, the atom, step, and redox economy of a new synthetic method represent key parameters for the measure of its efficiency.1 Consequently, cascade isomerization reactions are highly attractive due to their redox-neutral, atom-economical nature, and their ability of converting readily available materials to more complex target molecules. The catalytic isomerization of allylic alcohols, particularly, has proven to be a powerful tool to deliver synthetically valuable carbonyl compounds with a highly efficient procedure.2 Various transition metal catalysts have been developed for this transformation.3 Highly enantioselective isomerization of β-substituted primary allylic alcohols has also been documented in the literature.4,5 In a related effort to readily access novel, complex structures, the development of remote functionalization of alkenes has witnessed great advancement in recent years.6,7 These processes involve transition metal-catalyzed alkene functionalization followed by a long-range isomerization through a chainwalking pathway. With the achievement of stereocontrol, these transformations provide a unique advantage of establishing stereogenic centers that are distant from the resultant functionality. © 2018 American Chemical Society
Combining the power of the two strategies, the isomerization of remote alkenyl alcohols has also attracted much attention in recent years. However, only a few successful catalytic systems were reported in the literature for such a challenging process. While early success with ruthenium catalysis was disclosed by the Grotjahn group,8 the Mazet group has introduced a couple of Pd-catalyzed systems for a general and highly efficient long-range isomerization of alkenyl alcohols of different substitution patterns.9 Importantly, a few examples of enantioselective isomerization of primary homoallylic alcohols with moderate to good enantioselectivity was also documented in these works (Scheme 1a). To the best of our knowledge, the isomerization of remote alkenyl secondary alcohols with enantiocontrol remains elusive in the literature. Two key challenges need to be addressed in order to achieve efficient and stereoselective isomerization of functionalized secondary alcohols. First, the reactivity of these compounds are much lower than their primary alcohol counterpart, making the achievement of both reactivity and selectivity extremely difficult. Second, it is preferable to use the readily available Received: July 3, 2018 Published: October 15, 2018 14647
DOI: 10.1021/jacs.8b07007 J. Am. Chem. Soc. 2018, 140, 14647−14654
Article
Journal of the American Chemical Society Scheme 1. Catalytic Enantioselective Isomerization of Alkenyl Alcohols
Table 1. Optimization of Homoallylic Alcohol Isomerizationa
a
Reactions were carried out with 0.1 mmol of 1a, 2.5 mol % [Rh(COD)2]BF4, 5 mol % chiral ligand, 30 mol % base, and 50 mg of 4 Å MS in 0.5 mL of solvent. bIsolated yield. cDetermined by chiral HPLC analysis. d48 h reaction time.
racemic substrates;10 thus, a stereoconvergent transformation needs to be realized instead of a simple kinetic resolution.11 Our group has focused on the development of catalytic enantioselective redox-neutral transformations for efficient chemical synthesis. In particular, we are interested in stereoconvergent transformations that convert readily available racemic alcohols to valuable enantioenriched products.12 Very recently, we introduced the first enantioselective isomerization of secondary allylic alcohols to deliver chiral ketones bearing a tertiary α-stereogenic center.13 Such a process is capable of converting readily available, racemic alcohols to the synthetically valuable chiral ketones in a stereoconvergent fashion. Herein, we present the first catalytic enantioselective isomerization of remote alkenyl secondary alcohols to deliver chiral ketones bearing a β- or γ-stereocenter in high yields and enantioselectivity (Scheme 1b). This Rh-catalyzed process utilizes commercially available catalysts and a simple procedure, and operates on both homoallylic and bishomoallylic secondary alcohols. For the former case, an intriguing pathway of oxidative kinetic resolution followed by enantioselective alkene reduction is established, while for the bishomoallylic alcohols, a significant ligand effect is identified, resulting in an efficient alkene isomerization followed by isomerization of the alkenyl alcohols.
To further improve the yield of 2a by using ligand L7, screening of solvents, concentration, and other reaction parameters was performed. The use of TBME as the solvent was beneficial, leading to a full conversion to 2a, however, at the cost of reduced enantioselectivity (entry 9). Different inorganic and organic bases were evaluated, from which the usage of DABCO produced 2a in 72% yield and 84% ee (entry 10). The recovered 1a was also found to be highly enantioenriched (98% ee). With a prolonged reaction time of 48 h, a high yield of 88% and high ee of 84% for 2a were finally achieved with this stereoconvergent isomerization reaction (entry 11). The excellent enantioselectivity obtained for the recovered 1a pointed to the possibility of a highly efficient oxidative kinetic resolution. When DBU was used as the base, the reaction could be easily controlled at ∼50% conversion. Both 2a and recovered 1a were obtained in excellent ee of 90% and 98%, respectively (entry 12). Therefore, either kinetic resolution or enantioconvergent isomerization of homoallylic alcohols could be achieved. Remarkably, the same catalytic system promotes both alcohol oxidation and alkene reduction steps with a high level of enantiocontrol. We first examined the scope of enantioselective isomerization of homoallylic alcohols via the kinetic resolution
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RESULTS AND DISCUSSION Isomerization of Homoallylic Alcohols. We initiated our studies by using homoallylic alcohol 1a as the model substrate and commercial Rh complex and Ag2CO3 as the catalysts (Table 1).13 Preliminary screening quickly established that slightly elevated temperature of 50 °C was necessary to achieve reasonable reactivity. Through systematic screening of chiral ligands (as exemplified in entries 1−8), the JosiPhos analog L7 proved to be optimal for enantioselectivity of 2a, albeit with a low yield (entry 7). It is interesting to note that the recovered 1a was also enantioenriched, indicating a kinetic resolution of the racemic substrate. 14648
DOI: 10.1021/jacs.8b07007 J. Am. Chem. Soc. 2018, 140, 14647−14654
Article
Journal of the American Chemical Society approach (Scheme 2). For the model substrate 1a, the S factor was determined to be >50. A methyl substitution on either aryl
Scheme 3. Rh-Catalyzed Convergent Isomerization of Homoallylic Alcoholsa
Scheme 2. Rh-Catalyzed Kinetic Resolution of Homoallylic Alcohols via Isomerizationa
a
See Supporting Information for details. bThe reaction was carried out at 70 °C.
substituted homoallylic alcohol (R2 = furan) was tested, the ketone product was obtained with a good 86% ee, albeit with very low efficiency (
