9.4: Diastereoselective Addition to Aldehydes and Ketones
- Page ID
- 23989
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\(\newcommand{\avec}{\mathbf a}\) \(\newcommand{\bvec}{\mathbf b}\) \(\newcommand{\cvec}{\mathbf c}\) \(\newcommand{\dvec}{\mathbf d}\) \(\newcommand{\dtil}{\widetilde{\mathbf d}}\) \(\newcommand{\evec}{\mathbf e}\) \(\newcommand{\fvec}{\mathbf f}\) \(\newcommand{\nvec}{\mathbf n}\) \(\newcommand{\pvec}{\mathbf p}\) \(\newcommand{\qvec}{\mathbf q}\) \(\newcommand{\svec}{\mathbf s}\) \(\newcommand{\tvec}{\mathbf t}\) \(\newcommand{\uvec}{\mathbf u}\) \(\newcommand{\vvec}{\mathbf v}\) \(\newcommand{\wvec}{\mathbf w}\) \(\newcommand{\xvec}{\mathbf x}\) \(\newcommand{\yvec}{\mathbf y}\) \(\newcommand{\zvec}{\mathbf z}\) \(\newcommand{\rvec}{\mathbf r}\) \(\newcommand{\mvec}{\mathbf m}\) \(\newcommand{\zerovec}{\mathbf 0}\) \(\newcommand{\onevec}{\mathbf 1}\) \(\newcommand{\real}{\mathbb R}\) \(\newcommand{\twovec}[2]{\left[\begin{array}{r}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\ctwovec}[2]{\left[\begin{array}{c}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\threevec}[3]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\cthreevec}[3]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\fourvec}[4]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\cfourvec}[4]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\fivevec}[5]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\cfivevec}[5]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\mattwo}[4]{\left[\begin{array}{rr}#1 \amp #2 \\ #3 \amp #4 \\ \end{array}\right]}\) \(\newcommand{\laspan}[1]{\text{Span}\{#1\}}\) \(\newcommand{\bcal}{\cal B}\) \(\newcommand{\ccal}{\cal C}\) \(\newcommand{\scal}{\cal S}\) \(\newcommand{\wcal}{\cal W}\) \(\newcommand{\ecal}{\cal E}\) \(\newcommand{\coords}[2]{\left\{#1\right\}_{#2}}\) \(\newcommand{\gray}[1]{\color{gray}{#1}}\) \(\newcommand{\lgray}[1]{\color{lightgray}{#1}}\) \(\newcommand{\rank}{\operatorname{rank}}\) \(\newcommand{\row}{\text{Row}}\) \(\newcommand{\col}{\text{Col}}\) \(\renewcommand{\row}{\text{Row}}\) \(\newcommand{\nul}{\text{Nul}}\) \(\newcommand{\var}{\text{Var}}\) \(\newcommand{\corr}{\text{corr}}\) \(\newcommand{\len}[1]{\left|#1\right|}\) \(\newcommand{\bbar}{\overline{\bvec}}\) \(\newcommand{\bhat}{\widehat{\bvec}}\) \(\newcommand{\bperp}{\bvec^\perp}\) \(\newcommand{\xhat}{\widehat{\xvec}}\) \(\newcommand{\vhat}{\widehat{\vvec}}\) \(\newcommand{\uhat}{\widehat{\uvec}}\) \(\newcommand{\what}{\widehat{\wvec}}\) \(\newcommand{\Sighat}{\widehat{\Sigma}}\) \(\newcommand{\lt}{<}\) \(\newcommand{\gt}{>}\) \(\newcommand{\amp}{&}\) \(\definecolor{fillinmathshade}{gray}{0.9}\)Advancements in Acyclic Stereochemical Models
- Cram's Model: J. Am. Chem. Soc., 1952, 74, 5828-5835.
- Karabatsos Model: J. Am. Chem. Soc., 1967, 89, 1367-1371.
- Felkin Model: Tetrahedron Lett., 1968, 2199-2204.
Cram Model (Cram's Rule)
Cram's rule suggests that we should place the largest substituent of the adjacent stereocenter eclipsed with the R group (H in below depiction) of the carbonyl. The Nucleophile then attacks from the less hindered face of the carbonyl to provide the major product.
While Cram's Rule correctly predicts many reactions, it has its limitations. The conformation of the starting material leads to an eclipsed product after the initial addition which is unfavorable due to increasing torsional strain through the reaction coordinant, and the model works best when the RL is phenyl.
Felkin Model
One flaw with the Felkin model is that it predicts the wrong transition state for reactions with aldehydes:
Felkin-Anh Model
Anh and Eisenstein provided key advancements to Felkin's model. First, they suggested that the nucleophile attacked the Carbonyl at a larger bond angle that 90 °. The HOMO-LUMO interaction between the NU and Carbonyl requires a larger bond angle, estimated between 100-110 °. This angle is now refered to as the Burgi-Dunitz angle, after the two crystallographers who proposed it (Acc. Chem. Res., 1983, 16, 153-161.).
Anh and Eisenstein also hypothesized that there was favorable overlap between the forming C–Nu bond with the antibonding orbital of C–RL. This would allow for two possible conformers during the addition. One conformer requires the nucleophile to approach over the Rs substituent, whereas the other conformer allows the nucleophile to approach over the smallest substituent, in this case hydrogen. The least hindered trajectory (red arrows) is less sterically demanding in the transition state and leads to the favored product.
This model suggests that the substituent with the best acceptor antibonding orbital will be oriented antiperiplanar to the forming C–Nu bond.
Houk has provided theoretical support for staggered transition states: J. Am. Chem. Soc., 1982, 104, 7162-7166. and Science, 1986, 231, 1108-1117.
Padden-Row provides theoretical support for the Felkin-Anh-Eisenstein Model: J. Chem. Soc., Chem. Commun. 1990, 456-458.
This model applies to many alpha-chiral carbonyls and many nucleophiles, including hydrides.
Borane reducing agents do not follow this trend. In general, non-spherical nucleophiles are unreliable in the Felkin-Anh analysis.
Cram Chelate
alpha-substituents that can chelate a metal allow cause a reversal in selectivity:
Path A shows our typical Felkin-Anh selective model while Path B shows the transition state leading to the minor diastereomer in a Felkin-Anh analysis. Depending on the metal and the RL (RL = OR in figure), a reversal of selectivity can occur due to chelation of the metal between the carbonyl oxygen and RL. Chelation controls the conformation of the transition state and causes the nucleophile to attack from the opposite face.
In the below table, BOM-protected alcohols show high preference for the chelate product while the TBDPS-protected alcohol almost exclusively forms the Felkin-Anh product. Thus, we can control the product distribution based on the protecting group or solvent.
Tetrahedron Lett., 1982, 23, 2355-2358.
Work from the Keck lab has also shown that, while solvent and R-grouops affect the selectivity, the choice of Lewis Acid can also drastically change the selectivity. In general, the lewis acid must be good at chelation in order to form the Cram Chelate product. A few examples of good lewis acids for chelation are MgBr2, ZnBr2, TiCl4, and SnCl4. As seen in the table below, BF3•OEt2 does not chelate and provides the Felkin-Anh product.
Tetrahedron Lett., 1984, 25, 265-268.
Padden-Row provides theoretical support for the Cram Chelate model: J. Chem. Soc., Chem. Commun., 1991, 327-330.