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. 2018 Feb 21;140(7):2643-2655.
doi: 10.1021/jacs.7b13296. Epub 2018 Feb 8.

Enantioselective Synthesis of Trisubstituted Allenyl-B(pin) Compounds by Phosphine-Cu-Catalyzed 1,3-Enyne Hydroboration. Insights Regarding Stereochemical Integrity of Cu-Allenyl Intermediates

Youming Huang  1 , Juan Del Pozo  1 , Sebastian Torker  1 , Amir H Hoveyda  1
Affiliations

Enantioselective Synthesis of Trisubstituted Allenyl-B(pin) Compounds by Phosphine-Cu-Catalyzed 1,3-Enyne Hydroboration. Insights Regarding Stereochemical Integrity of Cu-Allenyl Intermediates

Youming Huang et al. J Am Chem Soc. .

Abstract

Catalytic enantioselective boron-hydride additions to 1,3-enynes, which afford allenyl-B(pin) (pin = pinacolato) products, are disclosed. Transformations are promoted by a readily accessible bis-phosphine-Cu complex and involve commercially available HB(pin). The method is applicable to aryl- and alkyl-substituted 1,3-enynes. Trisubstituted allenyl-B(pin) products were generated in 52-80% yield and, in most cases, in >98:2 allenyl:propargyl and 92:8-99:1 enantiomeric ratio. Utility is highlighted through a highly diastereoselective addition to an aldehyde, and a stereospecific catalytic cross-coupling process that delivers an enantiomerically enriched allene with three carbon-based substituents. The following key mechanistic attributes are elucidated: (1) Spectroscopic and computational investigations indicate that low enantioselectivity can arise from loss of kinetic stereoselectivity, which, as suggested by experimental evidence, may occur by formation of a propargylic anion generated by heterolytic Cu-C cleavage. This is particularly a problem when trapping of the Cu-allenyl intermediate is slow, namely, when an electron deficient 1,3-enyne or a less reactive boron-hydride reagent (e.g., HB(dan) (dan = naphthalene-1,8-diaminato)) is used or under non-optimal conditions (e.g., lower boron-hydride concentration causing slower trapping). (2) With enynes that contain a sterically demanding o-aryl substituent considerable amounts of the propargyl-B(pin) isomer may be generated (25-96%) because a less sterically demanding transition state for Cu/B exchange becomes favorable. (3) The phosphine ligand can promote isomerization of the enantiomerically enriched allenyl-B(pin) product; accordingly, lower ligand loading might at times be optimal. (4) Catalytic cross-coupling with an enantiomerically enriched allenyl-B(pin) compound might proceed with high stereospecificity (e.g., phosphine-Pd-catalyzed cross-coupling) or lead to considerable racemization (e.g., phosphine-Cu-catalyzed allylic substitution).

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Figures

Figure 1
Figure 1
Influence of electrophile concentration and/or identity on er. Reactions were carried out under N2 atm; >98% conv in all cases (determined by analysis of 1H spectra of unpurified product mixtures (±2%)). Yields (in parentheses) are for isolated and purified allenyl boronate products, and are based on the limiting reagent (±5%). Enantioselectivity was determined through HPLC analysis (±1%). See the Supporting Information for details. dan = naphthalene-1,8-diaminato.
Figure 2
Figure 2
Fluxional nature of Cu–allenyl complexes (enantioselective Cu–H addition, propargyl-to-allenyl isomerization and racemization). Free energy values were obtained at the MN15/Def2TZVPPthf(SMD)//M06L/DF-Def2SVPthf(PCM) level; pc, π-complex; ts(CuHa), transition state for copper hydride addition; ts(rac), transition state for racemization; ts(iso), transition state for π-allyl isomerization; Cu–p, Cu–propargyl intermediate; Cu–a, Cu–allenyl intermediate. See the Supporting Information for details.
Figure 3
Figure 3
Competition between racemization and trapping with H–B(pin); free energy values were obtained at the MN15/Def2TZVPPthf(SMD)//M06L/DF-Def2SVPthf(PCM) level; ts(rac), transition state for racemization; Cu–a, Cu–allenyl intermediate; tsα, transition state for α-addition to H–B(pin); tsγ, transition state for α-addition to HB(pin); BHa, borohydride adduct. See the Supporting Information for details.
Figure 4
Figure 4
Comparison of various modes of racemization; free energy values were obtained at the MN15/Def2TZVPPthf(SMD)//M06L/DF-Def2SVPthf(PCM) level; ts(rac), transition state for racemization; Cu–a, Cu–allenyl intermediate; a–B(pin), allenyl–B(pin) product; phos-a, phosphine adduct with allenyl–B(pin) product; Ar = p-F3CC6H4; uncat = uncatalyzed. See the Supporting Information for details.
Figure 5
Figure 5
Low temperature 31P NMR experiment to investigate the isomerization of Cu–amajor to Cu–aminor; all measurements where performed at −50 °C in thf–d8. See the Supporting Information for details.
Figure 6
Figure 6
Relevance of metal–allene racemization to bis-phosphine–Pd-catalyzed cross-coupling; free energy values have been obtained at the MN15/Def2TZVPPthf(SMD)//M06L/DF-Def2SVPthf(PCM) level; P2 = (phenyl)bpe; ts(rac), transition state for racemization; ts(iso), transition state for π-allyl isomerization; Pd–p, Pd–propargyl intermediate; Pd–a, Pd–allenyl intermediate; ts(re), transition state for reductive elimination; pc, π-complex. See the Supporting Information for details.
Scheme 1
Scheme 1
Relevant Previous Investigations
Scheme 2
Scheme 2
Goals of This Study
Scheme 3
Scheme 3
Synthesis of Trisubstituted Allenyl Boronates. Scope I: Aryl-Substituted 1,3-Enynes as Substrates aReactions were carried out under N2 atm. Conv, >98% in all cases, determined by analysis of 1H spectra of unpurified product mixtures (±2%). Yields for purified allenyl products (±5%). Enantioselectivities were determined by HPLC analysis. bReaction time was 40 h. Experiments were run in duplicate or more. See the Supporting Information for details. pin = pinacolato.
Scheme 4
Scheme 4
Synthesis of Trisubstituted Allenyl Boronates. Scope II: Alkyl-Substituted 1,3-Enynes as Substrates aReactions were carried out under N2 atm. Conv, >98% in all cases except for 4f (67%), determined by analysis of 1H spectra of unpurified product mixtures (±2%). Yields for purified products (±5%). Enantioselectivities were determined by HPLC analysis. bReaction time was 40 h. Experiments were run in duplicate or more. See the Supporting Information for details.
Scheme 5
Scheme 5
Efficient and Diastereoselective Addition to an Aldehydea aCarried out under N2 atm. Conv (>98% in all cases) determined by analysis of 1H spectra of unpurified product mixtures (±2%). Yields for purified products (±5%). Enantioselectivities were determined by HPLC analysis. Experiments were run in duplicate or more. See the Supporting Information for details.
Scheme 6
Scheme 6
Retention/Loss of Kinetic Selectivity Depends on the Type of Reactiona aCarried out under N2 atm; >98% conv in both cases (determined by analysis of 1H spectra of unpurified product mixtures (±2%)). Yields are for purified products (±5%). Enantioselectivity was determined by HPLC analysis. Experiments were run in duplicate or more. See the Supporting Information for details.
Scheme 7
Scheme 7
Relevance to a Previously Reported Methoda aReactions to obtain were carried out under N2 atm; >98% conv in both cases (determined by analysis of 1H spectra of unpurified product mixtures (±2%)). Yields are for purified products (±5%). Enantioselectivity was determined by HPLC analysis. Experiments were run in duplicate or more. See the Supporting Information for details.
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