Stereoselective Synthesis: Comprehensive Advanced Organic Chemistry Study Guide

Designing a Synthetic Strategy: The Golden Rules

• Rule 1: Make the synthesis as short as possible.

• Rule 2: Use only disconnections corresponding to known, reliable reactions.

• Rule 3: Disconnect C–X bonds, particularly focusing on two-group disconnections.

• Rule 4: Disconnect C–C bonds according to the functional groups (FG) present in the molecule. If possible:

  • Aim for the greatest simplification.

  • Disconnect in the middle of the molecule.

  • Disconnect at a branch point.

  • Disconnect rings from chains.

  • Use symmetry if it is present.

• Rule 5: Choose the disconnection corresponding to the highest yielding reaction (if known).

• Rule 6: Disconnect back to recognizable starting materials.

• Key Reactions for Targeted Synthetic Approaches:

  • Esterification.

  • Wittig reaction.

  • Horner-Wadsworth-Emmons (HWE) reaction.

Review of Isomerism and Stereochemical Terms

• Isomers: General category for different compounds with the same molecular formula.

  • Constitutional Isomers: Differ in the connectivity of atoms.

  • Stereoisomers: Same connectivity, different spatial arrangement.

    • Configurational Isomers: Due to restricted rotation (e.g., cis- or trans- diastereomers).

    • Diastereomers: Stereoisomers that are not mirror images of each other.

    • Enantiomers: Non-superimposable mirror-image molecules.

• Chirality:

  • A molecule is chiral if it is not superimposable on its mirror image (e.g., right and left hands).

  • Achiral: A molecule that possesses a plane of symmetry, dividing it into two pieces that are exact mirror images.

  • Examples: $S$-limonene (smells like lemons) and $R$-limonene (smells like oranges).

Origins and Significance of Chirality

• Chiral Pool: Nature is a primary source of chirality. Most natural products contain chiral centers because enzymes are responsible for introducing chirality.

• Methods of Asymmetric Synthesis:

  • Chiral Pool Starting Materials: Using sugars or amino acids to control relative stereochemistry.

  • Chiral Reagents or Catalysts: Introduces chirality into the product and controls absolute stereochemistry.

  • Chiral Auxiliaries: Attached to the substrate to give diastereomeric products.

  • Chiral Resolution: Exploiting different reactivities of enantiomers under specific conditions.

• Biological Importance:

  • FDA Policy (1992): Urges companies to evaluate both racemates and pure enantiomers for new drugs.

  • Dobutamine: The $S$-enantiomer exhibits $\beta_1$-agonist and $\beta_1$-agonist activity, while the $R$-enantiomer is an $\beta_1$-antagonist. In a racemic mixture, the $\beta_1$ effects are cancelled.

  • Thalidomide: The $R$-enantiomer treats morning sickness; the $S$-enantiomer is a teratogen (causes birth defects). The compound can racemize in vivo.

  • Receptor Interaction: Different stereoisomers interact with receptors differently because functional groups point into different parts of the receptor pocket. Example: (–)-epinephrine vs. (+)-epinephrine vs. N-methyldopamine.

Configuration and Prochirality

• Absolute Configuration: The exact 3D arrangement of atoms. Historically, before absolute configuration could be determined, D-(+)-glyceraldehyde was defined as having the OH group on the right in a Fischer projection.

• Relative Configuration: Shows stereochemical relationships (e.g., cis/trans) without specifying absolute $R/S$ configuration.

• Prochirality:

  • A carbon atom is prochiral if changing one group (e.g., replacing one $H$ with $D$) generates a chiral center.

  • Enantiotopic groups: Groups that, when replaced, yield enantiomers. Enzymes can distinguish between these.

  • Stereofaces: Faces of a molecule (e.g., carbonyls) are classified as Re face (O, $CH_3$, H in clockwise order) or Si face (anticlockwise order).

• Diastereotopicity: Seen in methylene hydrogens where replacement leads to diastereomers. These hydrogens are chemically and spectroscopically distinct.

Conformers and Resolution

• Conformational Isomers: Stereoisomers interconvertible by rotation about single bonds at room temperature. Lower energy conformers are more populated.

• Biological Relevance of Conformation:

  • Thyroid Hormones (T3 and T4): Derived from L-tyrosine. Restricted rotation gives T3 a specific shape (phenyl rings at $120^\text{o}$) required for receptor interaction.

• Physical Resolution:

  • Crystallization: Enantiomers may crystallize under different conditions or in different forms.

  • Chromatography: Utilizes chiral stationary phases (HPLC, GC, TLC).

• Chemical Resolution:

  • Chiral Resolving Agents: Reacting a racemate with a single chiral reagent (e.g., rac-tartaric acid with a (+)-amine) to form diastereomers with different physical properties (solubility).

  • Mosher's Acid: Used in NMR spectroscopy to determine purity.

• Kinetic Resolution:

  • One enantiomer reacts faster than the other ($k_S / k_R > 20$).

  • Reaction must be stopped before completion.

  • Maximum yield is 50% unless the unwanted enantiomer is racemized.

  • First used by Pasteur with Penicillium species.

Measuring Chiral Purity

• Measurement Tools:

  1. Specific Rotation: Measured using a polarimeter. [\text{\alpha}]_D = \frac{\text{Observed rotation (degrees)}}{\text{Path length (dm)} \times \text{concentration (g/ml)}}.

  2. Enantiomeric Excess (e.e.): $\% \text{ major enantiomer} - \% \text{ minor enantiomer}$. Example: 95% enrichment = 90% e.e.

• Determination Methods:

  • Mosher Esters: React with Mosher acid and use $^1H$ or $^{19}F$ NMR to measure diastereomer ratios.

  • Literature Comparison: $e.e. = \frac{[\alpha]_D \text{ (observed)}}{[\alpha]_D \text{ (literature)}} \times 100$.

Diastereoselective Hydride Reductions and Additions

• Stereoselectivity vs. Stereospecificity:

  • Stereoselective: Preferred formation of one stereoisomer over another.

  • Stereospecific: The mechanism determines the product configuration based on the reactant configuration (e.g., $S_N2$, $E2$, Bromination of alkenes).

• Hydride Reagents: $LiAlH_4$ and $NaBH_4$ act as sources of nucleophilic hydride ($H^-$). They perform nucleophilic substitution ($R-Br \rightarrow R-H$) and addition to carbonyls ($C=O \rightarrow C-OH$).

• Kinetic Control: Addition is irreversible ($\Delta G$ is large and negative). Product distribution is determined by the transition state (TS) energy barriers ($G^\#$).

• Felkin-Ahn Model: Used to predict addition to \text{\alpha}-chiral aldehydes/ketones.

  1. Draw Newman projections with the Large (L) substituent perpendicular to the carbonyl.

  2. Approach of hydride at a $107^\text{o}$ angle (Bürgi-Dunitz trajectory).

  3. The major product results from the trajectory passing the Small (S) group rather than the Medium (M) group.

• Chelation Control:

  • Occurs when a second electronegative heteroatom (e.g., \text{\alpha}-alkoxy) is present and a metal (e.g., $Mg, Zn$) can bridge the two atoms.

  • Chelation control is usually more selective than Felkin-Ahn. Nucleophiles attack from the least hindered face of the chelated ring.

Chiral Aldol Reactions

• Basics: Forms two new stereogenic centers, potentially yielding 4 stereoisomers ($2^n$). Products are categorized as syn or anti diastereomers.

• Mechanism: Deprotonation forms an enolate, which acts as a nucleophile attacking an aldehyde, followed by protonation.

• Stereochemical Control Factors:

  1. Enolate Geometry:

     • Z-enolates (cis): Formed when the O-Metal and alkyl group are on the same side. Lead to syn products.

     • E-enolates (trans): Lead to anti products.

  2. Metal Choice: Boron enolates ($R_2BOTf$) are more selective than Lithium enolates because the shorter $B-O$ bond leads to a more "tightly held" and sterically sensitive 6-membered cyclic transition state (Zimmerman-Traxler model).

  3. Evans Aldol: Use of chiral oxazolidinone auxiliaries on boron enolates. These can completely override aldehyde stereochemical preferences, providing high diastereofacial selectivity.

  4. Double Asymmetric Induction: When both partners are chiral, they are "matched" (selectivity reinforces) or "mismatched" (selectivity opposes).

• Mukaiyama Aldol Reaction:

  • Involves silyl enol ethers and a Lewis acid (e.g., $TiCl_4, BF_3 \times OEt_2$).

  • Proceeds via an acyclic transition state. Selectivity is controlled by the size of the Lewis acid.

• Chiral Boron Ligands: Developed by Paterson ($Ipc_2BOTf$), Masamune, and Corey for high e.e. without auxiliaries.

Asymmetric Hydroboration

• Process: addition of $H-B$ across a double bond (syn-addition). Chemically equivalent to anti-Markovnikov addition of $H_2O$.

• H.C. Brown (Nobel 1979): Discovered the process. Boron adds to the least substituted carbon due to steric and electronic factors.

• Reagents:

  • BH3 complexes: With THF, ethers, or amines.

  • Hindered Reagents: 9-BBN, Disiamylborane, Thexylborane. These enhance regioselectivity.

  • Transition Metal Catalysis: Using Catecholborane or Pinacolborane with Rhodium catalysts (Wilkinson's catalyst) can reverse or enhance selectivity.

• Enantioselective Reagents:

  • $(Ipc)_2BH$ (DIP-chloride precursor): Derived from \text{\alpha}-pinene. Effectively discriminates faces of $Z$-alkenes but performs poorly on $E$-alkenes.

  • Current limitations include substrate variability; best results are seen with vinyl arenes and electron-rich double bonds.

Epoxidation and Dihydroxylation

• General Epoxidation:

  • Reagents: Peracids (m-CPBA), peroxides with transition metals, or alkaline $H_2O_2$ for \text{\alpha, \beta}-unsaturated ketones.

  • Hydroxyl-Directed: Hydroxyl groups hydrogen-bond to the oxidant, delivering it to the syn face (e.g., allylic alcohols).

• Sharpless Asymmetric Epoxidation (AE):

  • Components: $Ti(OiPr)_4$, chiral tartrate ester ($DET$ or $DIPT$), and $tBuOOH$.

  • Stereochemistry: (+)-DET delivers oxygen from the bottom face (when the allylic alcohol is drawn in a specific orientation), (–)-DET from the top face.

  • Kinetic Resolution: Steric hindrance in the transition state allows for reacting away one enantiomer of a racemic allylic alcohol while leaving the other pure.

• Jacobsen Epoxidation:

  • Utilizes Mn(salen) complexes and $NaOCl$.

  • Does not require an allylic alcohol; works well for cis-alkenes.

  • Additives like amine N-oxides stabilize the $Mn(IV)$ oxo species and increase e.e.

• Sharpless Asymmetric Dihydroxylation (AD):

  • Standard Method: Catalytic $OsO_4$ with NMO as a co-oxidant (syn-addition).

  • Asymmetric Version: Uses Osmium with dimeric cinchona alkaloid ligands (DHQ or DHQD) on a phthalazine template.

  • Reagents: AD-mix \alpha (contains DHQ) and AD-mix \beta (contains DHQD).

  • Additives: $MeSO_2NH_2$ is added to accelerate the hydrolysis of the osmate ester intermediate.

Questions & Discussion

• Q: How many stereoisomeric products are possible in an Aldol reaction?

• A: $2^n = 2^2 = 4$ possible stereoisomers as both the aldehyde and enolate possess faces.

• Q: What is the best modern method to determine e.e.?

• A: Formation of a "Mosher ester" followed by NMR spectroscopy to measure the ratio of resulting diastereomers.

• Q: Why do amines make borane less reactive?

• A: Borane forms Lewis acid-base adducts with amines which are stable; alkyl boranes or boron-oxygen complexes are generally more refined for controlled hydroboration.