Overview of the Topics to be Covered in
CHEM 330
Table of Contents
A. Introduction 2
B. General Principles for the Construction of 1,3- Dioxygenated Assemblies 6
C. Construction of 1,3-Dicarbonyl Systems 12
D. Preparation and Alkylation of Carbonyl Enolates 29
E. Conjugate Addition Chemistry 64
F. Construction of β-Hydroxycarbonyl Assemblies 82
G. Construction of 1,3-Diol Systems 114
H. Pericyclic Reactions: Diels-Alder Chemistry 116
CHEM 330 p.2
A. INTRODUCTION
Course objective: to learn modern technology for the stereocontrolled assembly of molecules of current biomedical relevance
Importance of complex molecules in the biopharmaceutical industry of the 21st century
Evolution of the complexity of pharmaceutical molecules during the past century:
The first 100 years
HO H H OAc S N O COOH COO NH2 Aspirin - Bayer, ca. 1880 Thienamycin - Merck, ca. 1980
N OH H OH N N N COOH O
Indinavir - Merck, ca. 1995
The future
OH
OH O O OH O O
NH2 OH
Discodermolide - Novartis, 2004 CHEM 330 p.3
H H H H O O OH OH H O O H O O O O O O H H H H H H OH H O H O O O O H Halichondrine H O H H Me OH O
H H H N O O 3 O O H H H H MsO O O H O O H Eribulin mesylate O (Eisai, 2010)
Ubiquitous presence of the 1,3-dioxygenated functionality in molecules of biomedical interest
Three types of such 1,3-dioxygenated functionality: 1,3-dicarbonyl, 1,3-hydroxycarbonyl, 1,3-dihydroxy:
O O OH O OH OH
R1 R3 R1 R3 R1 R3 R2 R2 R2 1,3-dicarbonyl 1,3-hydoxycarbonyl 1,3-dihydroxy (= β-dicarbonyl) (= β-hydroxycarbonyl) "type A" "type B" "type C"
The 1,3-dioxygenated functionality as a logical starting point for the exploration of modern synthetic methodology.
Principle: only a particular configuration of the various stereocenters endows a molecule with the desired bioactivity. Consequently, technology for the assembly of 1,3- dioxygenated functionalities must be:
– diastereocontrolled (it must produce largely / only a given diastereomer of the requisite subunit), and
– enantiocontrolled (it must produce largely / only a given enantiomer of the above diastereomer) CHEM 330 p.4
Stereochemical aspects of 1,3-dioxygenated structures:
"Type A" structures possess a single stereogenic carbon; therefore, they may exist as a pair of stereoisomers that are enantiomers:
O O O O O O or R1 R3 may mean: R1 R3 R1 R3 R2 R2 R2 enantiomers
Chemical properties of 1,3-dicarbonyl structures:
Low pKa (10-14, average ≈ 12) of 1,3-dicarbonyl functionalities
Facile interconversion of the enantiomers of a 1,3-dicarbonyl structure through:
(i) reversible deprotonation:
enolate protonation from above: formation of enantiomeric structure B H O O easy, O O O R1 1 3 O R R 1 3 B H 2 H fast R R R R3 R2 R2 geometric plane B : symmetrical, planar structure enolate protonation from below: return to original structure
(ii) keto-enol tautomerism:
enol protonation from above: formation of enantiomeric structure
O O easy, O OH 1 O R OH 1 3 H 2 R R fast R1 R3 R R3 H 2 geometric R R2 plane symmetrical, planar structure enol protonation from below: return to original structure
Racemization: the interconversion of two enantiomers leading to a statistical, 50:50 mixture of the two.
The configuration of a 1,3-dicarbonyl structure is not controllable.
The preparation of 1,3-dicarbonyl structures presents no stereochemical issues, due to facile racemization.
CHEM 330 p.5
"Type B" structures incorporate a pair of stereogenic carbons; therefore, they may exist as a four possible stereoisomers:
O OH O OH O OH or or R1 R3 may mean: R1 R3 R1 R3 R2 R2 1 R2 2 Note: structures 1 and 3 and O OH O OH structures 2 and 4 are enantiomers; or structures 1 and 2, 1 and 4, 2 and 3, R1 R3 R1 R3 and 3 and 4 are diastereomers. R2 R2 3 4
the creation of 1,3-hydroxycarbonyl units presents significant stereochemical issues.
"Type C" structures incorporate three stereogenic carbons; therefore, they may exist as a eight possible stereoisomers (pairs of which may be enantiomers or diastereomers):
• a molecule containing n stereogenic centers can exist OH OH in 2n stereoisomeric forms * * R1 * R3 • a 1,3-dihydroxy unit contains three stereogenic centers 2 (starred C atoms) R 3 • 2 = 8 stereoisomers are possible
the preparation of 1,3-dihydroxy structures also comports major stereochemical issues.
Because the creation of 1,3-dicarbonyl compounds poses fewer / no stereochemical problems relative to the preparation of 1,3-hydroxycarbonyl or 1,3-dihydroxy structures, it is an ideal starting point to study the synthesis of 1,3-dioxygenated functionalities.
CHEM 330 p.6
B. General Principles for the Construction of 1,3-Dioxygenated Assemblies
Principle: bonds between atoms, in particular carbon atoms, are created by causing atoms of opposite polarity (+ / -) to interact.
Synthons: hypothetical, often electrically charged fragments needed in bond-forming operations
"Real" molecules that behave as carriers of individual synthons: reagents
Example of a reagent that carries a C atom possessing (+) character: CH3–I
Example of a reagent that carries a C atom possessing (–) character: CH3–Li.
Principle: the polarity of an atom is determined by the substituent(s) attached to it
Importance of the analysis of atomic polarity in charting a synthesis (selection of + and – synthons)
A substituent induces alternating polarity along a carbon chain, e.g.:
O (+) (+) (+)
(-) (-) (-)
Principle: the precise oxidation state of a carbon atom bearing a heteroratomic substituent has no influence on polarization: what counts is the nature of the heteroatom. Consequently, systems 1 and 2 below are equivalent in terms of polarity:
O OH (+) (+) (+) (+) (+) (+)
(-) (-) (-) (-) 1 2
Principle: in carbon chains incorporating multiple heteroatomic substituents, each substituent polarizes individual carbon atoms independently of other substituents.
The two O functionalities of a 1,3-dioxygenated system induce matching atomic polarity in the C atoms:
O O (+) (-) (+) (+) (-)(+)
Mismatched atomic polarity in, e.g., a 1,4 dioxygenated system:
CHEM 330 p.7
O (-) (+) (-) (+) (+) (-)(+) (-) O
Principle: the construction of a polarity-matched system is easier than the assembly of a polarity-mismatched structure.
Principle: in order to build a polarity-mismatched system, one must reverse the natural polarity of an atom.
Reversal of polarity or Umpolung
Synthons required for the construction of a 1,3-dicarbonyl system:
O O O O 1 3 R R R1 R3 2 R R2
O Derivatives of carboxylic acids (acid chlorides, esters, etc.) as carriers of R1
O
Carbonyl enolates as carriers of R3 R2
Possible construction of a 1,3-hydroxycarbonyl system ("type B" structure):
OH O OH O 1 3 R R R1 R3 2 R R2
OH Aldehydes as carriers of
Construction of a 1,3-diol system ("type C" structure): a special case of 1,3- hydroxycarbonyl construction, because a C=O group may be reduced to an OH with appropriate reagents:
OH OH OH O
R1 R3 R1 R3 R2 R2
Importance of carbonyl-based transformations in organic synthesis CHEM 330 p.8
C. Construction of 1,3-Dicarbonyl Systems
Carbonyl-based reactions as ideal starting points to explore modern synthetic methodology
Acid chlorides and anhydrides as generally unsuitable reagents (with a few exceptions and for reasons to be addressed later) for the synthesis of 1,3-dicarbonyl systems
Formation of 1,3-dicarbonyl (=β-dicarbonyl) structures by reaction of carbonyl enolates with esters: the Claisen condensation O O O O O O
R1 OEt R3 R1 R3 R1 R3 R2 EtO R2 R2
Claisen condensation of ethyl acetate:
2 CH -COOEt —[base]à CH -CO-CH -COOEt + EtOH 3 3 2 ethyl acetate ethyl acetoacetate
Approximate pKa's of representative organic molecules:
H–CH2-COOEt H–CH2-CO-CH3 EtO–H
pKa ≈ 25 pKa ≈ 20 pKa ≈ 17
Detailed step-by-step mechanism of the Claisen condensation of EtOAc promoted by EtONa
Use of pKa differences to estimate the position of the equilibrium in a proton transfer reaction Example: the deprotonation of CH3-COOEt with EtONa:
Na Na
EtO H–CH2-COOEt EtO–H + CH2-COOEt
pKa ≈ 25 pKa ≈ 17
–8 pkeq ≈ 25 – 17 = 8 Keq ≈ 10
Principle: equilibrium constants / pKa differences provide an approximate measure of the extent of deprotonation.
CHEM 330 p.9
—8 Example: for the above reaction, Keq ≈ 10 . Suppose also that the initial concentrations of EtOAc and base are identical and equal to 1 M. The extent of deprotonation of EtOAc under these conditions is roughly equal to the square root of Keq, i.e.:
–8 –4 [ CH2-COOEt ] ≈ Keq = 10 = 10
meaning that approximately 1 part in 10,000 of the quantity of EtOAc will be present as the enolate under these conditions (consult the handouts on pKa's posted on the course website for details of the calculation).
Principle: generally, acceptable reaction rates require an instant concentration of reactive intermediates (enolates, etc.) greater than about 10–5-10–6 M. Relationship between equilibrium constants and ΔG: the Gibbs equation:
ΔG = –n RT ln Keq
where n = number of moles, R = gas constant (=1.98•10–3 kcal/°K mol)
Principle: because changes in pKa are associated with ΔG's, one may use ΔpKa's to estimate whether a reaction step involving basic agents will be thermodynamically favorable or unfavorable:
Reminder: A step that produces a weaker base at the expenses of a stronger base is thermodynamically favorable (because ΔG < 0)
A step that produces a stronger base at the expenses of a weaker base is thermodynamically unfavorable (because ΔG > 0)
Thermodynamically unfavorable deprotonation of ethyl acetate with NaOEt and consequent reversibility of the process
The condensation of two molecules of ethyl acetate to form ethyl acetoacetate as a themodynamically unfavorable process
2 CH3-COOEt à CH3-CO-CH2-COOEt + EtOH ΔG > 0
Principle: mixing one equivalent of pure ethyl acetoacetate with one equivalent of pure ethanol in the presence of a catalytic amount of EtONa would induce a reverse Claisen condensation that will convert the starting components into two molecules of ethyl acetate (the thermodynamically more favorable state of the system):
– CH3-CO-CH2-COOEt + EtOH —[ cat. EtO ]—> 2 CH3-COOEt (overall ΔG < 0) "Active methylene:" a CH2 group with unusually acidic H's due to the presence of two flanking activating groups (e.g., two C=O's)
CHEM 330 p.10
Active methylene compounds: molecules such as ethyl acetoacetate that incorporate an active methylene
Acidity of the methylene protons of ethyl acetoacetate: pKa ≈ 12
Deprotonation of ethyl acetoacetate (more generally, of the 1,3-dicarbonyl product of a Claisen condensation) by EtONa: a thermodynamically favorable event (ΔG < 0) that approximately cancels out the thermodynamic disadvantage incurred in the earlier stages of the process
Overall stoichiometry of the Claisen condensation:
– – 2 CH3-COOEt + EtO —> CH3-CO-CH( )-COOEt + 2 EtOH (overall ΔG ≈ 0)
The Claisen condensation as a readily reversible process when carried out under the above conditions
Proton transfer from a molecule of EtOH to the anion of the 1,3-dicarbonyl formed under the above conditions as an event that triggers reversal of the Claisen condensation
Le Chatelier's principle
Removal of EtOH from the medium as a possible way to drive the reaction forward
Possible way to drive a Claisen condensation to completion: removal of EtOH from the medium by:
(a) continuous fractional distillation of EtOH (old method, painstaking) (b) reaction with an appropriate agent
Possible deprotonation of EtOH with a suitably strong base
Sodium hydride (NaH), potassium hydride (KH) as carriers of hydride ion, H–
– H as the conjugate base of H2
– Estimated pKa of H2 ≈ 40, therefore, H is a very strong base
Stoichiometry of the Claisen condensation promoted by NaH
O O O 2 + NaH + EtONa OEt OEt Na
no EtOH present à no opportunity for reversal Basic, but non-nucleophilic, nature of the H– carried by NaH
CHEM 330 p.11
Principle: an anionic species (H–, carbanions, etc.) may be induced to express basic reactivity (proton affinity) or nucleophilic reactivity (carbon affinity) depending on the nature of the metallic cation that accompanies it
Thermodynamically favorable deprotonation of an ester by hydride ion:
– – H–CH2-COOEt + H —> CH2-COOEt + H–H
pKa ≈ 25 stronger base weaker base pKa ≈ 40
15 ΔpKa = – 15 à Keq ≈ 10 ; ΔG25*C ≈ – 20 kcal/mol << 0
However: kinetic effects cause H– in NaH to react very slowly with an ester.
Rapid reaction of NaH with hydroxylic agents such as alcohols or water, leading to formation of alkoxides or of hydroxide. Such reactions evolve flammable H2 gas.
Use of catalytic amounts of EtOH in Claisen condensations promoted by NaH:
O NaH O O (+ EtONa) OEt cat. EtOH OEt Na
Principle: it is generally easier to isolate organic substances as electrostatically neutral species, rather than in ionic form
Protonation of the enolate of the 1,3-dicarbonyl product of a Claisen condensation by treatment with mild aqueous acid (e.g., 1N aq. HCl):
O O mild O O (+ EtONa) OEt OEt H O+ 3 easier to handle Na than the enolate
Principle: it is generally easier to isolate organic substances as electrostatically neutral species, rather than in ionic form
Protonation of the enolate of the 1,3-dicarbonyl product of a Claisen condensation by treatment with mild aqueous acid (e.g., 1N aq. HCl):
mild O O O O easier to handle Na (+ EtONa) OEt than the enolate OEt H O+ 3
Claisen condensation of esters other than ethyl acetate, e.g:
CHEM 330 p.12
O O O 1. NaH, OEt OEt cat. EtOH ethyl propionate + 2. mild H3O
Failure of those Claisen condensations, which — when carried out under the conditions seen in class — lead to a product unable to undergo deprotonation, e.g.:
O 1. NaH, O O OEt ( ΔG > 0 ) cat. EtOH OEt + 2. mild H3O ethyl isobutyrate
Lactones: cyclic esters
Macrolactone ("macrolide") antibiotics, e.g. narbomycin (structure below), erythromycin, and congeners: molecules composed of multiple propionic acid units that have been linked together through Claisen-type condensations (therefore called polypropionate substances).
O
the antibiotic narbomycin: a typical polypropionate. Group R is a sugar residue. Notice the presence of what in class we have called "type A" and "type B" structures in this molecule. O O-R Imagine opening the lactone ring: this leads to . . . O O
OH O OR O O OH O O O OR O O
OH OH
the open form of narbomycin plausible precursor of narbomycin: the green O functions (alcohols or carbonyls) are ultimately removed by the organism that produces the antibiotic OH O O O OR O O
OH
propionate subunits in the narbomycin precursor
Importance of modified macrolides in modern antibiotics research
Desirability of Claisen condensations between two different esters
CHEM 330 p.13
Cross-Claisen condensation: one leading to the union of two different esters, e.g.:
O O O O base OEt + OEt OEt R1 R2 R1 R2
Formation of mixures of products upon attempted cross-condensation of two different — but similar — enolizable esters under conditions of reversible enolization of the ester (e.g., with NaH / cat. EtOH)
example: the attempted synthesis of A by cross-Claisen condensation of ethyl propionate with ethyl butyrate:
O O 1. NaH O O cat. EtOH OEt OEt OEt + 2. mild H3O ethyl butyrate ethyl propionate A: desired product (enolate of propionate added to intact butyrate)
BUT: 3 other products are likely to form:
O O O O O O
OEt OEt OEt
undesired product undesired product undesired product (enolate of propionate (enolate of butyrate (enolate of butyrate added to propionate) added to butyrate) added to propionate)
Principle: to achieve a selective cross-Claisen condensation one cannot operate under conditions in which product distributions is determined by the thermodynamic preference of the system ("thermodynamic control" – as seen in the Claisen condensations discussed so far). Instead, one must operate under conditions in which:
(i) the rate at which a particular product forms is much faster than that at which other products might form; and
(ii) no opportunity exists for thermodynamic equilibration of the initial product mixture.
but what is that determines the rate of a reaction?
Principle: the rate of a reaction is determined solely by the magnitude of the activation energy barrier, regardless of the thermodynamic properties (=thermodynamic stability) of the products:
CHEM 330 p.14
consider the reaction diagram below, which shows a set of reactants that could undergo conversion into either product 1 or to product 2 through transition states A and B, respectively. It so happens that the activation energy for the reaction leading to ‡ ‡ product 1, ΔE A, is smaller that that for the reaction leading to product 2, ΔE B.
Product 1 will form faster than product 2.
energy
B ΔΔE‡ ΔE‡ B A ΔE‡ A
Ereactants Reactant(s)
Prod. 1 Prod. 2 react. coord.
The absolute rate of each reaction (= how much of each product forms per unit time ‡ ‡ under a given set of experimental conditions) will depend on ΔE A and ΔE B only.
The relative rate of the reaction (= how much more product 1 forms per unit time ‡ relative to product 2 under the same set of conditions) will depend on ΔΔE only.
‡ Formulas that correlate ΔE 's and rates (e.g., the Arrhenius equation) will be discussed in more advanced courses.
Principle: in all cases of interest in CHEM 330 (exceptions will be discussed in more advanced courses), the rate of a reaction (i.e. its ΔE‡) is independent of the thermodynamic stability of the products. Therefore, the fast-forming product (product 1 in the example above) may be either thermodynamically more stable or less thermodynamically stable than the slow-forming one:
The reaction diagram below shows a case on which the faster-forming product happens to be thermodynamically more stable than (= favored over) the slower-forming product:
energy
B ΔΔE‡ ‡ A ΔE B ΔE‡ A
Reactant(s)
ΔE prods. Prod. 2
Prod. 1 react. coord. CHEM 330 p.15
This is a common case, but it is by no means the norm!!! Indeed, an equally common, and far more interesting, case is the following:
energy
B ΔΔE‡ ‡ A ΔE B ΔE‡ A
Reactant(s)
ΔE prods. Prod. 1
Prod. 2 react. coord.
the fast-forming product is now thermodynamically less stable than (= disfavored over) the slow-forming product. If the system depicted in the above diagram were made to react under conditions of irreversibility (= no thermodynamic equilibration of the ‡ products), then it will afford largely / nearly exclusively (depending on ΔΔE ) product 1.
• Under such conditions, the reaction is said to proceed under kinetic control, in the sense that the product distribution is determined solely by the rates at which individual products form
• Product 1 is said to be the kinetic product of the reaction
Principle: if the system depicted in the above diagram were to be perturbed in such a way that the reactions leading to the various products become reversible, then product 1 will be converted into product 2. At thermodynamic equilibrium, the ratio of product 2 over product 1 will be determined by the standard free energy difference between the two:
[Prod. 2] ΔE prods. ≈ ΔG° = – nRT ln K = – RT ln (for n = 1 mol) [Prod. 1]
• Product 2 is said to be the thermodynamic product of the reaction
General approach to the conduct of a cross-Claisen condensation under conditions of kinetic control:
O O O O ? OEt + OEt OEt R1 R2 R1 R2
i. convert the "R2" ester rapidly, completely and irreversibly into the enolate, e.g, with LDA, at low temperature (–78 °C)
CHEM 330 p.16
O O LDA, –78 °C Li OEt OEt grossly oversimplified rapid, irreversible depiction of an enolate R2 R2
Reminder: LDA (lithium diisopropylamide) is a strong, non-nucleophilic base prepared from diisopropylamine and BuLi (CHEM 213):
H Li rapid and N N + BuLi + Bu–H irreversible pKa ≈ 50 pKa ≈ 35-37
Rapid and irreversible deprotonation of enolizable esters and carbonyl compounds in general with LDA
ii. cause the above enolate to react rapidly, completely and irreversibly, at low temperature, with the "R1" component
iii. the "R1" component must not be provided in the form of an ester. Upon reaction, the ester would release EtO–, which can deprotonate the 1,3-dicarbonyl product and generate EtOH, which promotes the reverse reaction. Moreover.....
Tendency of the preformed lithium enolate of, e.g., an ethyl ester, to react with a second enolizable ethyl ester both by addition to the C=O (nucleophilic behavior) and by proton transfer (basic behavior):
O O mechanism a: EtO O O nucleophilic behavior O OEt OEt R1 R1 R2 R1 R2 OEt O desired H product H OEt O R2 O mechanism b: 1 undesired R + basic behavior OEt OEt products R2
Comparable (not necessarily equal, but similar) rates of addition and proton transfer under such conditions, and consequent formation of mixtures of products.
Principle: a successful cross-Claisen reaction requires the preformed enolate to react with an ester-like agent that:
a. is much more electrophilic than an ordinary ester
b. does not release a basic fragment, or it releases a fragment incapable of inducing reversibility
CHEM 330 p.17
Unsuitability (with a few exceptions) of acid chlorides in cross-Claisen condensations, due to interference from a variety of side reactions (ketene formation, O-acylation…)
Use of acyl cyanides and acyl imidazoles (= acid imidazolides) as convenient ester surrogates in cross-Claisen condensations:
O O R R N N CN
acyl cyanide acyl imidazole
Facile preparation acyl imidazolides and acyl cyanides from acid chlorides:
"imidazole": a common heterocyclic compound O N NH O O KCN R R N N R CN Cl acyl cyanide acyl imidazole
Direct formation of acid imidazolides from carboxylic acids and carbonyldiimidazole ("CDI", Staab reagent):
O O O R R + N N N N N N + CO2 + HN N OH carbonyl diimidazole acyl imidazole
Probable mechanism of the above reaction:
O O O R N N N N HN N N N O H O R O O O O O O O N N N N acyl imidazole + N N H O N N (product) R R R HN N
O ±H+ O N NH HO N N O N N H + CO2
unstable ... CHEM 330 p.18
General mechanism for the reaction of an enolate with an acyl cyanide or an acyl imidazole (same as for the standard Claisen reaction):
O X O Li Li O COOEt X = N N or C N X 1 OEt 1 2 R 1 R R R fairly stable at low temp. (grossly oversimplified + structure of the enolate) H3O (workup) O COOEt + HN N or HC N R1 R2 isolated material
Li O + H3O O possible COOEt Z–H COOEt deproton. 1 2 (workup) R R R1 R2 (end-product isolated material of the reaction)
Some special cases of successful cross-Claisen condensations occurring under conditions of thermodynamic control:
Case a (very important): condensation of an enolizable ester with a non- enolizable one;
Case b (less significant): condensation of a more C–H acidic ester with a less acidic one;
Case c (less significant still): cross condensation between 2 enolizable esters that lead to only 1 kind of product capable of final deprotonation.
Case a (important): condensation of an enolizable ester with a non-enolizable one; e.g., Ar-COOEt ("Ar" = aryl group, such as a benzene ring, a pyridine, …), EtOCOOEt (diethyl carbonate), EtO-CHO (ethyl formate), EtOOC-COOEt (diethyl oxalate)...
Products from the reaction of, e.g. ethyl propionate, with the above esters:
O O O O O 1. NaH, OEt cat. OEt + OEt or EtO OEt or EtO H or EtO N O EtOH an aromatic 2. mild diethyl ethyl diethyl + ester carbonate H3O formate oxalate
CHEM 330 p.19
O O O O O O O O EtO OEt or EtO OEt or H OEt or OEt N O
Minimizing the self-condensation of the enolizable ester: slow addition thereof to a mixture of NaH/EtOH and non-enolizable ester:
Under these conditions, the instant concentration of the enolizable ester in the medium is so low that the self-condensation becomes statistically improbable.
The products of the above cross-Claisen reactions as valuable building blocks for the synthesis of various medicinal agents (more about this later)
Important use of carbonate, oxalate, and formate esters in "Claisen-like" condensations involving enolates of ketones, e.g., cyclohexanone:
1. NaH, cat. O O O O EtOH EtO OEt + EtO + 2. H3O workup O O O EtO OEt EtO O " O
O O O
EtO H " H
Case b (less significant): condensation of a more acidic ester with a less acidic one, e.g.:
O NaH, O O O + OEt OEt (cat. EtOH) OEt Ph Ph + ethyl acetate ethyl phenylacetate then H3O product formed pKa ≈ 25 selectively pKa ≈ 18
Case c (less significant still): cross condensation between 2 enolizable esters that lead to only 1 kind of product capable of final deprotonation.
Reminder 1: a Claisen condensations carried out under conditions of reversibility, and leading to a product unable to undergo deprotonation, will fail because of unfavorable ΔG; e.g.:
CHEM 330 p.20
O O O NaH ( G > 0) 2 OEt OEt Δ cat. EtOH
ethyl isobutyrate
Reminder 2: the Claisen condensation reverts easily when a non-enolizable β-ketoester is exposed to e.g., EtO– / EtOH:
EtO O O O O O EtONa O OEt + etc. EtO EtO EtO EtOH EtO
Example of case c: the reaction of ethyl propionate with ethyl isobutyrate:
O O NaH cat. EtOH OEt + OEt 4 products are theoretically possible: then mild + ethyl isobutyrate ethyl propionate H3O enolizable enolizable
O O O O (a) (b) OEt OEt
enolate of propionate has reacted with intact isobutyrate propionate has reacted with itself
O O O O (d) (c) OEt OEt
enolate of isobutyrate has reacted with intact propionate isobutyrate has reacted with itself
However compounds (c) and (d) do not form under these conditions, because they cannot undergo the final deprotonation that drives the Claisen condensation toward the products.
Unsuitability (with a few exceptions) of acid chlorides in cross-Claisen condensations, due to interference from a variety of side reactions [ketene formation...]
Special cases of successful cross-Claisen condensations of acid chlorides: reaction with stabilized (pKa < 10) carbonyl enolates, especially with enolates of active methylene 1 2 compounds (R –CO-CH2-CO–R )
The Yonemitsu reaction: a technologically important method for the conversion of an acid chloride into a β-ketoester of the type R-CO-CH2-COOEt. CHEM 330 p.21
Meldrum's acid: a type of cyclic malonic ester that exhibits enhanced C–H acidity (pKa ≈ 4) relative to ordinary malonic esters (pKa ≈ 14)
O H O Meldrum's acid: pKa ≈ 4 H O O
Base-promoted acylation of the anion of Meldrum's acid with an acid chloride:
O O O O O O O Et3N R1 Cl O + Et3NH Cl 1 O pKa ≈ 12 O R O O O O pKa 4 ≈ Et3N-H
Thermal decomposition of acylated Meldrum's acids in alcohol solution:
O EtOH (or O O other alcohol) O O 1 R1 O heat to reflux R OEt O
note: we will discuss the mechanism of this reaction later on in the course
Practical importance of simple β-ketoesters of the type R-CO-CH2-COOEt in synthetic organic chemistry.
Mono- and di-alkylation of β-ketoesters of the type R-CO-CH2-COOEt using bases such as NaH, or even K2CO3
Double alkylation of β-ketoesters such as ethyl acetoacetate with 2 different alkyl halides; e.g.:
O O O O O O O O K2CO3 SN2 K2CO3 EtO EtO EtO EtO Br Br ethyl Ph acetoacetate Br Ph Ph
Preparation of non-enolizable β-ketoesters that are generally unavailable by direct Claisen condensation run under reversible conditions: case above, or bis-alkylation with the same alkyl halide
CHEM 330 p.22
O O O O O O 2 equiv. NaH, SN2 EtO EtO EtO 2 equiv. MeI
ethyl acetoacetate H3C I O O (base) O O EtO EtO H3C I
Synthesis of cyclic compounds via β-ketoesters such as R-CO-CH2-COOEt. E.g.:
O O O O O O R NaH R R OEt OEt OEt + I I I
Approximate relative rates of ring formation in the second step of above process:
O O O O n = total number of atoms in the ring n = 3 rel. rate ≈ 105 n = 6 rel. rate = 1 R OEt R OEt 4 10–2 7 10–2 X n 5 10 ≥ 8 v. slow
Decarboxylation of β-ketoesters as an avenue to ketones:
O H O H O+, heat O O 3 3 1 COOEt 1 R + CO R 1 R 2 R2 R3 (ca. 100°C) R O + EtOH R2 R3 R2
Examples:
O O O O O O aq. HCl aq. HCl OEt OEt reflux reflux
O O O R aq. HCl OEt R reflux
CHEM 330 p.23
The Krapcho reaction: a mild method for the decarboxylation of β-ketoesters:
O O O Na X, H2O 2 1 1 R R OMe R + (some) Me–X + CO2 2 3 R R DMSO, heat R3 R2, R3 may be X = Cl, Br, I, CN alkyl or H
Possible mechanisms for the Krapcho reaction
Intramolecular Claisen condensation: the Dieckmann reaction, e.g.:
O + mild H3O NaH O O OEt cat. Na workup COOEt COOEt COOEt EtOH diethyl adipate
Dieckmann reactions are governed by the same principles that direct Claisen condensations, e.g.:
(i) In theory, the Dieckmann reaction of the diester shown below could lead either to product a or to product b:
COOEt NaH (EtOH) O + O + then H3O COOEt COOEt in principle a b COOEt
In fact, only a forms, because a is the only product that can undergo final deprotonation. Recall, it is this deprotonation that provides the thermo- dynamic driving force for the reaction.
(ii) If we were to make b independently and treat it with EtONa / EtOH, it would isomerize to a:
NaOEt, O O COOEt then H O+ 3 COOEt b a
Scope of the Dieckmann reaction with respect to ring size of the product:
1. NaH, cat. EtOH O COOEt n = number of atoms n in the ring + COOEt 2. mild H3O COOEt
CHEM 330 p.24
n = 3, 4: the reaction fails because of ring strain.
n = 5, 6: the reaction works well
n = 7 the reaction is marginal
n > 7 the reaction fails because of unfavorable kinetics of the intramolecular process (slower) vs. the bimolecular one (faster). In part, this has to do with problematic conformational interactions that develop when the substrate attempts to "fold back" onto itself to form a ring. High dilution may promote ring formation in favorable cases.
note: in CHEM 330 we are only interested in Dieckmann reactions leading to the formation of 5/6 membered rings
Significance of the Dieckmann reaction for the creation of ring structures commonly found in substances of biomedical interest
Steroids: hormones involved in the regulation of a large number of biological processes and possessing the general structure shown below:
Me R Me R C Me H D C H D A H H B A H H HO B H HO "ordinary" steroids exhibit an aliphatic estrone: a typical aromatic A-ring steroid. A-ring. Group R may be many things These steroids are important female hormons
Difficulties encountered in the isolation of steroid hormones from natural sources and consequent interest in a chemical synthesis of such compounds starting in the 1940's
Decalin and perhydroindane ("hydrindane") subunits of steroids: cis and trans ring fusion
R = H, Me R R R R
H H H H trans-fused decalin cis-fused decalin trans-fused hydrindane cis-fused hydrindane
Energetically more favorable trans-ring fusion in decalin
R R trans-isomer: trans-isomer: less energetic more energetic more stable, less stable, more easier to make difficult to make H H CHEM 330 p.25
Energetically unfavorable trans-ring fusion in hydrindane (especially when R = Me) due to bond angle strain (make molecular models!!)
R R trans-isomer: strained. cis-isomer: almost strain- less stable, more difficult free. more stable, easier to to make make H H
Problematic formation of a trans junction between rings C and D of steroids
Me R C Me H D A H H B HO H
Possible approach to the creation of the C-D ring system of a steroid: prepare such a molecular subunit in the form of trans-decalin, then somehow break the ring to form a diester and carry out a Dieckmann condensation to build a 5-membered ring!
ring C future ring D Me Me Me O [ ? ] COOEt Dieckmann H H H COOEt COOEt [ ? ] rest H H H H H H of the molecule
Oxidative ring cleavage of cyclic ketones, e.g., by ozonolysis of enol derivatives or by treatment with hot concentrated HNO3
O O–E Me 1. base Me Me 1. O3 COOH (remainder of 2. suitable the molecule) 2. H2O2 E + COOH H H H H
hot HNO3
Claisen-Dieckmann avenue to trans C-D ring motifs of steroids, e,g:
O Me Me COOH EtOH an easy-to-make oxidative H trans-decaline- H cleavage COOH + based ketone: H H H H H
CHEM 330 p.26
Me 1. NaH, Me O hot aq. COOEt cat. HCl H H COOEt (today one COOEt EtOH would probably H H + H H 2. H3O do a Krapcho) trans-hydrindane !! O Me ketone may be Me R converted into H H a variety of R H H substitutuents H H
A-value of a group, G (see table of A-values on CHEM 330 website, "handouts" page): the energy difference between the equatorial and axial conformation of a monosubstituted chair-cyclohexane carrying group G:
equatorial G: G The energy difference axial G: between the two less energetic G more energetic more stable H conformers is the H less stable A-value of group G
The A-value of a group G as twice the magnitude of a gauche-butane interaction in a system such as CH3–CH2–CH2–G. For example, the A-value of a Me group is. ca. 1.8 kcal/mol, because:
• gauche-butane contains 0.9 kcal/mol more energy than anti-butane (energy minimum) • an axial Me group experiences two gauche-butane interactions with ring carbons: Me Me A-value of a Me group: 2 x 0.9 = 1.8 kcal/mol H H
Reasons for the greater energy content of cis– vs. trans-decalin: presence of three additional gauche-butane type interactions:
axial bonds cis-decalin contains 3 additional gauche-butane interactions relative to trans-decalin: H H H H H H
each gauche-butane interaction is worth ca. 0.9 kcal/mol; therefore cis-decalin contains ca. 0.9 x 3 = 2.7 kcal/mol more energy than trans-decalin
Heterocyclic systems such as pyridine, pyrimidine, pyrazole, etc., as common subunit of pharmaceutical agents
CHEM 330 p.27
R4 R1 N R5 N N N NH and many more R2 R4 R1 R3 R1 R3 R3 R2 R2 pyridine pyrimidine pyrazole
Principle: 1,3-dicarbonyl compounds and congeners, which are available by Claisen, cross-Claisen, and Dieckmann condensation reactions, are valuable intermediates for the synthesis of heterocyclic compounds of interest in modern medicine.
Principle: the construction of heterocyclic systems often involves the formation of imines (=Schiff bases). These are produced upon the condensation of carbonyl compounds with appropriate primary amines (see CHEM 203 notes):
2 2 R R1 R 1 R –NH2 O N 3 3 R – H2O R
example 1: synthesis of pyrazoles by reaction of 1,3-dicarbonyls with hydrazine:
H2N NH2 hydrazine N NH imagine a N N non-aromatic O O 1 3 R R 1 3 R R 1 3 2 tautomer ... R R R R2 R2 pyrazole: aromatic this substance would instantly tautomer rearrange to the aromatic tautomer "type A" 1,3-di-O functionality!
example 2: the synthesis of pyrimethamine analogs
imagine a N non-aromatic N H1N Cl H1N Cl N tautomer ... N NH2 NH pyrimethamine this substance would instantly originally developed rearrange to the aromatic tautomer as an antimalarial
NH2 O H2N + Cl NH C guanidine N Nitriles are similar to esters in behavior ... Special cases of successful cross-Claisen condensations of acid chlorides: reaction of acid chlorides with enolate-like carbanions obtained by deprotonation of nitriles:
CHEM 330 p.28
LDA, then O Cl Cl NC EtCOCl NC
then . . .
Cl Cl
Ar Ar Et N Et NH CN N NH N N NH O 2 + NH2 NH2 N N H2N NH guanidine NH2 NH2
CHEM 330 p.29
D. Preparation and Alkylation of Carbonyl Enolates
Significance of enolate alkylation reactions in the synthesis of compounds of current biomedical interest
Reaction of enolates with electrophilic agents: the question of C- vs. O-reactivity:
O enolate expresses O R E C-reactivity R generic enolate of any carbonyl (symbol for compound (ester, ketone, resonance) 1,3-dicarbonyl, etc.) E+ enolate E expresses O O O-reactivity R R
"Ambident" character of enolates = their ability to react at C as well as at O
Irreversible nature of the alkylation of an enolate
Significance of the ambident reactivity of enolates in irreversibile reactions such as alkylation process
Principle: it is generally inappropriate to attempt the derivatization — especially the C- alkylation — of a carbonyl compound by generating the enolate slowly and reversibly in the presence of an electrophile. This promotes undesirable side reactions such as multiple C-alkylation, as well as reaction of the basic agent with the electrophile.
Technical aspects of the derivatization of enolates:
• the carbonyl compound is first deprotonated rapidly, completely, and irreversibly with a suitably strong base. With simple esters, ketones, nitriles, etc. (pKa ≈ 20 – 25) LDA (pKa ≈ 37) or related bases are commonly used, often in tetrahydrofuran (THF) as the solvent.
tetrahydrofuran (THF): a convenient, inexpensive solvent widely used in organic chemistry O
• both the deprotonation of the carbonyl substrate and the subsequent reaction of the enolate with a suitable electrophile are carried out at low temperature (typically –78 °C: the temperature of a Dry Ice-acetone bath) to minimize proton-transfer reactions and to ensure the survival of the highly reactive enolate
Conduct of reactions involving enolates of simple carbonyl compounds under conditions of kinetic control CHEM 330 p.30
Principle: a multitude of factors, some of them rather subtle, control the C- vs. O- reactivity of an enolate. Three such factors that have a major influence on the reactivity of enolates are, in order of increasing importance:
• the nature of the metallic counterion that accompanies the enolate (significant)
• the solvent (very significant)
• the nature of the electrophile that reacts with the enolate (most significant)
Influence of the metallic counterion: C-reactivity is more pronounced in enolates incorporating more electronegative, and consequently more strongly Lewis acidic, metal ions, such as Li+. O-reactivity is more pronounced in enolates containing more electropositive, less strongly Lewis acidic metal ions such as K+
Li is smaller and more electronegative than K, therefore: • short, stronger O–Mt bond • long, weaker O–Mt bond • less strongly polarized • more strongly polarized • lower e– density around O R O Li R O K • higher e– density around O greater C-reactivity greater O-reactivity
Effect of solvent: C-reactivity is more pronounced in enolates prepared in mildly Lewis basic (=weakly coordinating) solvents, such as tetrahydrofuran (THF). O-reactivity is more pronounced in enolates prepared in strongly Lewis basic solvents (=strongly coordinating), e.g., DMSO, HMPA, DMPU and the like.
O DMSO S Me Me
HMPA (hexamethylphosphoric triamide) as a very polar, strongly Lewis basic solvent
O NMe HMPA P 2 Me2N NMe2
Toxic and carcinogenic properties of HMPA and use of dimethyl propylene urea (DMPU) as a safer alternative:
O
DMPU N N
Urea: a compound of formula H2N–CO–NH2, and by extension, a functional group containing the N–CO–N arrangement of atoms CHEM 330 p.31
Influence of the solvent on the degree of aggregation of enolates:
enolates prepared in weakly coordinating solvents, such as THF, exist in solution as aggregates. Thus, many carbonyl enolates prepared by deprotonation with LDA in THF (–78°C) are tetrameric. The tetramer displays a cubic core of alternating Li and O atoms:
O R Li O • C more exposed • O less exposed & strongly R O Li O bound to 3 Li+ ions, so weak O Li R O e– density around O Li O greater C-reactivity O R
note: diisopropylamine (in lieu of THF) may also ligate Li in the above tetramer
enolates prepared in strongly coordinating solvents, such as DMSO, HMPA, DMPU... exist in solution as monomers:
(S) • O more exposed & bound O to only 1 Mt+, so greater e– R O Mt O density around O (S) greater O-reactivity O (S)
"Naked" enolates: essentially free enolate anions existing in equilibrium with the monomeric form of the enolate in a strongly coordinating solvent:
S S S : S : = strongly R O Mt S R O S Mt S coordinating solvent S S naked enolate
"Ambident" reactivity of enolates: their ability to react either at C or at O
Nature of the electrophile: this is by far the most significant factor that determines C- vs. O-reactivity. The table below summarizes the C- vs. O-reactivity of enolates toward a range of common electrophiles of interest in CHEM 330 and in modern synthetic organic chemistry.
CHEM 330 p.32
type of (intermediate - of no electrophile C-reactivity interest to us) O-reactivity
alkyl halides and X = I, Br X = Cl, OTs X = OSO3R congeners, R-CH2–X (substantially primary) X = leaving group
epoxides O
acyl derivatives O X = halogen X = OR', CN, N N O R X X = O R others
sulfenyl & selenenyl halides R-S–Cl R-Se–Cl trialkylsilyl halides (extremely important) R3Si–Cl
Note: the reasons why, under conditions of irreversibility, particular Electrophiles prefer to react at the C terminus of an enolate while others react at O are manifold, complex, and not fully understood. Such preferences are often interpreted in terms of Hard / Soft Acid – Base (HSAB) theory. In CHEM 330 we are not concerned about the rationale for the C- vs. O-preference of such electrophiles. We simply accept the \ data in the table as fact.
Examples:
!- esters Br COOEt
O O–Li LDA, THF PhSe–Cl OEt Se COOEt OEt Ph – 78°C O–SiMe3 OEt a typical ester (aggregates) Me3Si–Cl CHEM 330 p.33
!- ketones
O–SiMe cyclohexanone: 3 O a typical ketone O
Br O Me Si–Cl 3 LDA O O Me THF – 78°C Se Ph PhSe–Cl O–Li Ac 2O
O O O
O OMe (aggregates) OEt O O
MeO Cl EtO CN [Mander reagent]
Inconsequential nature of the ambident (= C vs. O) reactivity of enolates in the context of Claisen-Dieckmann reactions occurring under conditions of reversibility. Example: the case of ethyl propionate:
O
OEt EtO O O O hypothetical O O O OEt O-reactivity O OEt OEt OEt OEt reversible etc.
• can react with EtO to regenerate the starting ester • can react with with the enolate in a Claisen mode
Significant nature of the ambident reactivity of enolates in the context of kinetically controlled, irreversible reactions of the latter
Interest of α-S and α-Se substituted carbonyls in modern organic synthesis:
• enhanced C–H acidity of α-S and α-Se substituted carbonyls: selective deprotonation and alkylation:
much more acidic than much more acidic than
O O O O O E 1. base H H PhS PhS H PhS OEt H OEt + 2. E
CHEM 330 p.34
• oxidation of sulfides to sulfoxides and of selenides to selenoxides with MCPBA (meta-chloroperoxybenzoic acid, the same reagent that is used to form epoxides from olefins) or with H2O2:
O O O PhS S MCPBA Ph
(or H2O2) a sulfide a sulfoxide
likewise: O O O PhSe O MCPBA Se MCPBA O O Ph PhS(e) OEt PhS(e) (or H2O2) (or H2O2) OEt a selenide a selenoxide
thermal instability of α-sulfoxy and — especially — α-selenoxy carbonyls
concerted thermal elimination of sulfoxides (T > 100°C) and — especially — of selenoxides (T > 30°C) as a valuable method for the introduction of olefins in direct conjugation with carbonyls
Ph O O Ph O O Se T > 30°C S T > 100°C O O H H O heat O OEt OEt S(e)Ph O
Importance of conjugated carbonyl compounds in modern organic chemistry
Enol esters and enol carbonates: structures obtained upon O-acylation of a carbonyl enolate:
O O O O an enol ester an enol (enol acetate carbonate Me in this case) OMe
Silyl enol ethers and silyl ketene acetals: compounds obtained upon O-silylation of the enolate of a ketone and of an ester, respectively:
CHEM 330 p.35
O–SiMe O–SiMe silyl enol ether 3 3 silyl ketene acetal derivative of derivative of cyclohexanone OEt ethyl propionate
Silyl enol ethers and silyl ketene acetals as stabilized "surrogates" of carbonyl enolates; i.e., relatively unreactive enolate analogs, which nonetheless can be caused to express enolate-like reactivity under appropriate conditions
unlike true metal enolates, silyl enol derivatives are:
(i) somewhat tolerant of water, air (O2), room temperature, etc. They may be stored, and in some favorable cases they may even be purified, e.g., by distillation.
(ii) unreactive toward electrophiles such as alkyl halides, other carbonyl compounds (aldehydes, etc.).
Mechanistic dichotomy in the reactivity of tertiary alkyl halides vs. trialkylsilyl halides:
Li O O SiMe3 Cl Si Cl O
+ (+ Li–Cl) elimination substitution: only: no only: no (+ Li–Cl) substitution reactive, elimination basic
Probable associative mechanism involved in substitution at a Si center [formation of a discrete pentacoordinated Si intermediate ("siliconate"), etc.]:
R R R Nu may be an enolate, alcohol, alkoxide, R Si L Nu Si L Nu Si R + L fluoride ion .... R R R R L is a generic leaving group; e.g., Cl, OR Nu discrete pentacoordinated intermediate
Principle: increasing steric bulk around the silicon atom retards the rate of nucleophilic substitution by retarding the rate of formation of the (presumed) siliconate intermediate
this step is R retarded by R R R Si L Nu Si L Nu Si R + L R steric bulk R R R around Si Nu
Silyl groups of common use in modern synthetic chemistry:
CHEM 330 p.36
increasing stability toward external agents (acids, bases, nucleophiles. etc.)
R–O Si R–O Si R–O Si R–O Si
trimethylsilyl triethylsilyl tert-butyldimethylsilyl tri-isopropylsilyl (TMS) ether (TES) ether (TBS) ether (TIPS) ether
note: because increasing steric bulk around the Si atom retards the rate of nucleophilic substitution (by retarding the rate of formation of the presumed siliconate intermediate), silyl ethers / enol ethers become progressively more resistant to the action of external agents as the steric bulk around the silicon atom increases
Silicon-centered protecting groups for alcohols: silyl ethers
R' R–O Si R' a generic silyl ether R'
Preparation of silyl ether derivatives of alcohols by reaction of R–OH with a trialkylsilyl chloride in the presence of a base, e.g., Et3N
R' R' Et3N R–O–H Cl Si R' R–O Si R' + Et3NH Cl R' R'
Cleavage of silyl ethers with F– ion through formation of a very strong Si–F bond
R' R' [H O] F– 2 R–O Si R' R' Si F + R–O R–O–H R' R' strong bond stronger bond
Tetrabutylammonium fluoride ("TBAF") as a convenient source of fluoride ion (soluble in common organic solvents)
Silyl enol ethers and silyl ketene acetals as stabilized "surrogates" of carbonyl enolates; i.e., relatively unreactive enolate analogs, which nonetheless can express enolate-like reactivity toward suitably activated electrophiles
unlike true metal enolates, silyl enol derivatives are:
(i) somewhat tolerant of water, air (O2), room temperature, etc. They may be stored, and in some favorable cases they may even be purified, e.g., by distillation.
(ii) unreactive toward electrophiles such as alkyl halides, other carbonyl compounds (aldehydes, etc.).
CHEM 330 p.37
Interest of silyl enol ethers / silyl ketene acetals in modern organic chemistry: under appropriate conditions, silyl enol derivatives may be induced to express nucleophilic reactivity at C, just like an ordinary metal enolate
Reaction of silyl enol ethers with aldehydes under catalysis by Lewis acids such as BF3: the Mukaiyama variant of the aldol reaction:
Me3Si Me3Si F3B O O F3B BF3 or O O O + other suitable H Ph H Ph H Ph Lewis acid much more much less unreactive toward electrophilic electrophilic plain aldehydes
Me3Si O OH aldol-type O O–BF3 Ph addition Ph
Interesting feature of silyl enol ethers: possibility of effecting C-alkylation with tertiary alkyl halides (impossible with true metal enolates), e.g.:
SiMe SiMe O 3 O 3 O Cl TiCl4 or + (+ Me3Si–Cl) other suitable TiCl Lewis acid 5 Friedel-Crafts-like mechanism
Regarding the O-alkylation of enolates (i.e., the reaction of carbon-based electrophiles at the O-terminus of enolates):
i. Generally speaking, the O-alkylation of enolates is not a technologically significant process — or certainly not as significant as the C-alkylation.
ii. A possible exception is the O-alkylation of enolates of active methylene compounds, which leads to building blocks for the preparation of heteocyclic compounds and other synthetically useful materials
O-alkylation of active methylene compounds with dialkyl sulfates as an avenue to synthetically useful intermediates, e.g.:
O MeO S OMe O O O OMe NaH O O O EtO EtO EtO Na CHEM 330 p.38
Application of the O-alkyation of the enolate of an active methylene compound in the synthesis of fecaenes:
OH HO O
a typical fecaene
Fecaenes as highly mutagenic, and probably carcinogenic, metabolites of fats present in human feces and associated with the incidence of colon cancer in subjects who consume a diet high in fats
Fats (= lipids): triesters of glycerol and long-chain acids, therefore also described as "triacylglycerols." Each type of fat incorporates a specific permutation of acyl groups:
OH Acyl chain O–CO(CH2)nCH3 General structure of HO OH CH3(CH2)nCO–O O–CO(CH2)nCH3 saturated fats (=lipids)
glycerol n ≥ 10 note • unsaturated fats (lipids) incorporate one or more cis-C=C bonds in the acyl chains • trans-fats incorporate trans--C=C bonds in the acyl chains
Synthesis of fecaenes:
OH O–TBS TBS = Si OH OH TBS–O OTs
H KH CHO K O O DMF CHO then:
active methylene O–TBS O–TBS K O O CHO CHO TBS–O OTs O–TBS
PPh 3 OH 1. O
(Wittig ) OH 2. TBAF
notice how the alkylation step is carried out: the electrophile is a tosylate (tends to react with enolates at O), the enolate counterion is K+ (the potassium counterion favors O- CHEM 330 p.39
alkylation), and the reaction is carried out in DMF (a very polar solvent with properties similar to those of DMSO; this type of solvent favors O-alkylation)
Dimethylformamide (DMF): a polar, aprotic solvent with properties similar to those of DMSO:
O
DMF N H
Conversion of silyl enol ethers to Li enolates by reaction with MeLi, e.g.:
O SiMe3 O Li MeLi (likewise for ester-derived + Me4Si silyl enol ethers)
C-Alkylation of carbonyl enolates as a fundamental C-C bond forming process in modern synthetic organic chemistry
Preparation and C-alkylation of enolates of the major classes of carbonyl and carbonyl- like compounds
Preparation of enolates of esters, nitriles, and tertiary amides with LDA and their C- alkylation
Inability of primary and secondary amides to form enolates due to initial deprotonation of the N–H group (pKa ≈ 15) and formation of a fairly energetic anion which resists further deprotonation:
O base O O R R R N N N H pKa ≈ 15
fairly energetic: R = H: primary amide resists further R = alkyl: secondary amide deprotonation
Ivanov enolates of carboxylic acids:
Br O LDA O LDA O COOH H O O O (1 equiv.) pKa ≈ 5 low-enegy anion: then aq. undergoes further Ivanov enolate workup deprotonation
CHEM 330 p.40
Difficulties encountered in the preparation of aldehyde enolates by deprotonation of aldehydes with LDA:
rate of deprotonation ≈ rate of aldol addition of the enolate to an intact aldehyde and consequent polymerization of the aldeyde under basic conditions
Imines (=Schiff bases): nitrogen analogs of carbonyls, e.g.: R O N
H H a carbonyl an imine compound
Temporary conversion of aldehydes to imine-type derivatives as way to suppress aldol- type reactions during deprotonation:
O H N–Z N–Z Z = alkyl; e.g. tert-Bu: an imine R 2 R Z = NMe2: a dimethylhydrazone H H – H2O any enolizable imine-type derivative aldehyde
cannot be converted cleanly easily and cleanly converted to an enolate with, e.g., LDA to an enolate with, e.g., LDA
Formation, deprotonation, and alkylation of tert-butylimine and N,N-dimethylhydrazones derivatives of aldehydes, e.g.:
H N 2 1. LDA N N R R MgSO4 2. O (e.g.) Br R H H2N N 1. LDA N N R NMe2 R NMe 2. 2 (e.g.) Br
Hydrolysis of imines and hydrazones as a method to retrieve the corresponing aldehyde:
aq. H+ ( + H N–G; G = tert-Bu, NMe ) N O 2 2 R G R H H
the overall result is equivalent to the alkylation of the enolate of the starting aldehyde
CHEM 330 p.41
Retrieval of aldehydes from N,N-dimethylhydrazones through ozonolysis (applicable so long as no interfering functionality, such as olefins, are present in the molecule)
The α-alkylation of aldehydes by the above methodology as a process of considerably lesser significance than the α-alkylation of other carbonyl compounds
"Enormous complexity" of the mechanism(s) of deprotonation of ketones
Deprotonation of ketones: the issue of regioselectivity with unsymmetrical substrates:
O O O base & / or likewise:
O O O base & / or
Olefin-like nature of enolates:
O O more significant less significant resonance struct. resonance struct.
Principle: just as in the case of an olefin, the thermodynamic stability of an enolate increases with increasing substitution around the C=C bond, e.g.:
O O O O more stable than: and more stable than: 3 substituents 2 substituents around C=C around C=C 4 substituents 3 substituents around C=C around C=C
Principle: treatment of an usymmetrical ketone of the type shown above with a weaker base that deprotonates the substrate slowly and reversibly (e.g., an alkoxide such as tert- BuOK) leads preferentially to the more substituted, more thermodynamically favorable enolate:
O tBuOK O–K O–K + small amounts of
O O–K O–K tBuOK + small amounts of
CHEM 330 p.42
Mechanistic rationale for formation of the more thermodynamically favorable enolate upon deprotonation of, e.g., 2-methylcyclohexanone with tBuOK (or with NaH/cat EtOH):
tBuO– (pKa ≈ 19) is insufficiently basic to deprotonate the ketone (pKa ≈ 20) completely and irreversibly. Enolate formation will occur under conditions of reversibility, permitting the accumulation of the more thermodynamically favorable enolate, T, at the expense of its isomer K:
O O O slow and slow and ROH + + RO + ROH reversible reversible
K - less stable: C T - more stable: minor enolate at equilibrium major enolate at equilibrium
In such a reversible reaction, the product ratio is determined solely by the energy difference between products T and K. In the present case, the majority of the molecular population of starting ketone will be channeled through the reaction pathway leading to enolate T, which becomes the major product.
energy
O Mt
O Mt K ΔE prods.
T
A reaction that proceeds under these conditions is said to be thermodynamically controlled. Enolate T may be described as the thermodynamic product of the deprotonation reaction (= thermodynamic enolate).
Principle: treatment of an unsymmetrical ketone of the type shown above with a strong (pKa > 30), hindered base that deprotonates the substrate rapidly and irreversibly (e.g. LDA and related agents) and that contains a Lewis acidic, oxophilic metallic counterion leads preferentially to the less substituted, less thermodynamically favorable enolate:
O O–Li O–Li LDA + small amounts of
CHEM 330 p.43
Mechanistic model (NOT "mechanism") for the deprotonation of ketones with, e.g., LDA (–78 °C, THF), resulting in formation of the thermodynamically less favorable enolate
Lewis acidic, oxophilic character of Li+
Probable first interaction of LDA with the substrate, e.g., 2-methylcyclohexanone: complex formation:
O Li O N + Li N
note: the formal (+) on the O atom enhances the acidity of adjacent protons by making the O more electron-attarcting. Moreover, the formal (–) on the Li atom enhances the basicity of the N atom by increasing the extent of N–Li bond polarization, thereby augmenting the electronic density on the N atom. Therefore, this activated complex is primed for proton transfer from C to N
Preferred conformation of the complex:
H H N O Li Me H
cyclohexane in a chair conformation Me group (A-value = 1.8) equatorial:
Principle: The σC-H orbital of the proton that is removed by the base must be aligned with the large lobe of the π*C=O orbital to permit maximum electron delocalization during proton transfer
dihedral only this H is angle = 0 properly aligned for deprotonation π *C=O H R σ C-H O H H
"Stereoelectronic" control in the deprotonation of a carbonyl compound: the reaction can only occur only if / when a specific orbital alignment is attained:
CHEM 330 p.44
dihedral The σC-H orbital of the proton that is removed only this H is angle = 0 by the base must be aligned with the large properly aligned lobe of the π*C=O orbital to permit maximum for deprotonation π *C=O electron delocalization during proton transfer. H R σ C-H O H H
The E2 reaction as an example of another process that proceeds under stereoelectronic control (anti-elimination)
Principle: in a cyclohexanone derivative, only the axial proton(s) satisfy the stereoelectronic requirements for deprotonation; i.e., a base can only abstract an axial H:
case of an acyclic ketone: case of a cyclohexanone:
dihedral angle = 0 only axial H's are only this H is properly aligned σ properly aligned for deprotonation H C-H for deprotonation H π *C=O H R H σ C-H O H O H H π *C=O
Greater likelihood of proton transfer in an intramolecular (=within the same molecule) sense than in a bimolecular one (= between two distinct molecules: e.g., one of the above complex and a second molecule of LDA)
Corollary: the above ketone-LDA complex must "fold back" onto itself in such a way that the N atom can abstract one of the axial protons
"Folding back" of the complex setting the stage for proton transfer through a chair-like 6- centered transition state
• Possible evolution of the LDA-ketone complex toward two transitions states:
The circled H and i-Pr groups are pseudo-axial relative to the red chair: Li N O–Li moderately energetic H H 1,3-diaxial-like interaction O fast and Me H irreversible Me equatorial: major product more stable less energetic transition state
CHEM 330 p.45
The circled Me and i-Pr groups are pseudo-axial N relative to the red chair: Li O–Li a severe 1,3-diaxial-like H H interaction subsists O fast and Me Me still equatorial H irreversible relative to the black chair: more stable more energetic minor product transition state
Reaction diagram for the regioselective deprotonation of 2-methylcyclohexanone with LDA:
the ketone-LDA complex, C, may evolve toward two energetically different transition states A (less energetic) and B (more energetic). If the reaction is irreversible, the product ratio will be determined solely by the energy difference between transition states A and B, regardless of the relative thermodynamic stability of products K and T. In the present case, the majority of the molecular population of C will be channeled through transition state A (less energetic than B), to give enolate K as the major product.
N Li H H O energy N Li Me H H H O Me B ΔE trans. sts. H A
C
Li K O N O–Li ΔE prods. T O–Li
react. coord. A reaction that proceeds under these conditions is said to be kinetically controlled. Enolate K may be described as the kinetic product of the deprotonation reaction, i.e., the kinetic enolate.
Extent of selectivity in the deprotonation of an unsymmetrical ketone:
The extent of selectivity, T / K for a reaction that proceeds under thermodynamic conditions (equilibration of enolates through proton exchange) will be defined by the energy difference between T and K (i.e., ΔE prods.) through the Gibbs equation:
ΔE ≈ ΔG° = – nRT ln k CHEM 330 p.46
where k is the ratio of products T and K
The extent of selectivity, T / K for a reaction that proceeds under kinetic conditions (irreversible deprotonation) will be defined by the energy difference between the transition states leading to T and K (i.e., ΔE trans. sts.), also through the Gibbs equation:
ΔE ≈ ΔG° = – nRT ln k
where k is the ratio of products T and K
Principle: equilibration of the enolates occurs through proton exchange mediated by a suitable "proton shuttle." As seen earlier for the deprotonation of ketones with, e.g., tert- BuOK, his may be a molecule of alcohol .....
O O O H–OR + RO
or one of intact ketone:
O O O O
H +
Possible formation of a thermodynamic enolate upon reaction of an unsymmetrical ketone such as 2-methylcyclohexanone with a molar defect of LDA: leftover ketone can act as a proton shuttle and catalyzes isomerization of the kinetic enolate to the thermodynamic one.
Use of a slight excess (1.1 equiv) of LDA at low temperature (–78 °C) in the deprotonation of ketones (and of carbonyl compounds in general) to minimize proton- transfer reactions and to preserve the integrity of the highly reactive enolates (which may decompose at or near room temperature) Principle: the deprotonation chemistry of unsymmetrical, acyclic ketones parallels that of their cyclic analogs
Deprotonation of acyclic ketones under thermodynamically controlled conditions (reversible deprotonation):
OK or O-Mt (Mt = K, Na, Li....) O
EtONa, or more substituted, O-Mt NaH - cat. EtOH less energetic ==> thermodynamically favored over etc.... CHEM 330 p.47
Deprotonation of acyclic ketones under kinetically controlled conditions (irreversible deprotonation):
(i) the acyclic ketone favors a conformation that maximizes σC-H-π*C=O hyperconjugation. As a consequence, the steric environment of the C=O group in an acyclic ketone is similar to that of the C=O group of a cyclic one. Example:
O H Me R σ C–H the steric environment of Me the C=O group is similar R O to that seen above for Me Me 2-methylcyclohexanone π* (R = alkyl) C=O
(ii) effects analogous to those seen earlier for the cyclic ketone will direct deprotonation toward the less substituted side of the carbonyl system:
N Li OLi H favored O H R H Me H Li R major pdt. O LDA O N R R N disfavored H OLi Me Me Li R R Me O severe steric interaction (minor pdt.)
Determination of the selectivity of enolate formation through O-silylation of the enolate mixture and analysis (e.g., by NMR) of the resulting mixture of silyl enol ethers:
O O O OTMS OTMS base Me3Si-Cl + +
reactive, air and relatively stable, moisture sensitive easily analyzed, e.g., by NMR
Conversion of silyl enol ethers into Li enolates with MeLi:
O–Li OTMS OTMS O–Li MeLi MeLi + Me Si Me4Si + 4
CHEM 330 p.48
Principle: regiochemically defined enolates are sometimes best obtained by MeLi cleavage of the corresponding silyl enol ethers, which may be purified to homogeneity by a number of methods
"Soft enolization" methods: techniques for the direct regioselective preparation of silyl enol ethers without passing through metal enolates ("hard enolization")
Direct formation of the kinetic (=less highly substituted) silyl enol ether from an unsymmetrical ketone by reaction with a trialkylsilyl triflate in the presence of a hindered amine base such as diisopropyl ethylamine ("Hünig's base")
O O–SiMe TMS-OTf 3 kinetic silyl enol ether N
Trifluoromethane sulfonic acid (triflic acid, CF3-SO2-OH, TfOH; pKa ≈ –10) as a "superacid" (= a Bronsted acid stronger than H2SO4)
The trifluoromethanesulfonate (triflate, TfO–) ion as an exceptionally good leaving group
Trialkylsilyl triflates, e.g., trimethylsilyl triflate, Me3SiOTf, as powerful silicon electrophiles
Mechanistic aspects of the formation of kinetic silyl enol ethers of ketones through "soft enolization" technology
Direct formation of the thermodynamic (=more highly substituted) silyl enol ether from an unsymmetrical ketone by reaction with, e.g., trimethylsilyl iodide in the presence of hexamethyldisilazane (a compound of formula Me3Si–NH–SiMe3): the Miller reaction:
O TMS-I O–SiMe3 thermodynamic H silyl enol ether Si N Si
Mechanistic aspects of the formation of thermodynamic silyl enol ethers of ketones through "soft enolization" technology: probable proton-catalyzed equilibration of kinetic silyl enol ethers with their thermodynamic isomers during the Miller reaction
Soft enolization of acyclic ketones: the principles developed above for the case of 2- methylcyclohexanone apply to the acyclic case as well; e.g.:
CHEM 330 p.49
OTMS TMS–I O TMS–OTf OTMS R R R H N TMS N TMS R = generic alkyl group
Deprotonation of α,β-unsaturated (= conjugated) carbonyl compounds
Important: bases cannot abstract protons connected to the olefinic α-position of a conjugated carbonyl compound, because resonance interactions force the C=O and C=C π-systems to be coplanar As a result, the dihedral angle θ between the axis of the olefinic α-C–H s bond and the axis of the lobes of the π*C=O orbital is ca. 90°. There is no overlap between σC–H and π*C=O orbitals à no deprotonation is possible
axis of the bases cannot abstract these protons dihedral angle large lobe θ ≈ 90° of the * O no overlap! π C=O H orbital H O Me O H axis of the OEt C–H bond
Definition of α, β, γ, … carbons of an α,β-unsaturated carbonyl compound
β O generic α,β-unsaturated R1 carbonyl compound R2 γ α
Dienolates from α,β-unsaturated esters: the case of, e.g., ethyl crotonate
O O O a base (e.g, LDA) can H OEt H remove one of these H OEt OEt protons, because .... H H : B the anion is resonance- a dienolate stabilized, just like an ordinary enolate
Deprotonation of α,β-unsaturated ketones (= enones), e.g., cyclohexenone: potential formation of two regioisomeric dienolates:
O O O deprotonation α' α deprotonation
of the α' position β of the γ position γ thermordynamically favored: thermordynamically disfavored: cyclohexenone: a typical enone resonance disperses charge resonance disperses charge over the α and γ carbons only over the α' carbon
CHEM 330 p.50
Deprotonation of enones under kinetic (non-equilibrating) conditions; e.g., with LDA: deprotonation occurs selectively at the α' position:
• proper representation of the half-chair conformation of cyclohexene and of cyclohexenone:
H H H H H H H H H H H H H H H H H H H H H H H H H H O H H H O H H H H H H H
• formation and fate of the enone-LDA complex:
only this H is properly aligned for N deprotonation OLi O H Li LDA H H H O H (excess) H H kinetic enone H enolate
Deprotonation of enones under thermodynamic (equilibrating) conditions: deprotonation occurs selectively at the γ position:
OLi O O O O appropriate conds. (e.g., ≈ slight defect of LDA, etc.) thermodynamic enone enolate -- a dienolate: the negative charge on the O atom is delocalized over two C=C bonds
Normal O-reactivity of dienolates of conjugated esters and ketones with, e.g., TMS-Cl:
O LDA O–Li TMS-Cl O–SiMe3
OEt –78 °C OEt OEt dienolate
CHEM 330 p.51
OLi O–TMS TMS-Cl
Normal O- and C-reactivity of kinetic enolates of enones
O–TMS O-reactive E+ O OLi e.g., TMS-Cl LDA O (excess) C-reactive E+ Me kinetic enone enolate e.g. CH3–I
Definition of α, β, γ carbon atoms of a dienolate:
OLi β OLi dienolate of a generic α R1 dienolate of α,β-unsaturated 2 cyclohexenone carbonyl compound γ α R β γ
Potential C-reactivity of a dienolate at the α-carbon or at the γ-carbon, e.g.:
β OLi β O β O α 1 γ R1 + Br could R1 and / or R 2 form R2 R2 γ α R γ α
product of product of α-alkylation γ-alkylation OLi O O α α α + Br could form and / or β product of product of γ γ γ α-alkylation γ-alkylation
Principle: C-alkylation of dienolates occurs selectively at the α-carbon, e.g.:
O β O Br β Br β OLi 1 α 1 γ R R R1 R2 R2 2 γ α γ α R
actual product CHEM 330 p.52
O OLi O Br Br α α
γ γ actual product
Molecular orbital based rationale for selective α-carbon reactivity of dienolates: greater electronic density at the α-carbon relative to the γ-carbon, and consequent greater α- nucleophilicity relative to γ- nucleophilicity
Principle of least motion: in the course of a reaction, molecules tend to minimize internal motion, i.e., the repositioning / displacement of atoms due to rehybridization.
Invoking the principle of least motion to rationalize the selective α-carbon reactivity of dienolates:
C,O go from singly bonded to doubly bonded: they move closer to each other
OLi O C,C go from doubly bonded to singy bonded: they move smaller extent of + α E , α-C E away from each other atomic motion: favored reaction C,C remain singly bonded γ ≈ no relative motion C,C remain doubly bonded ≈ no relative motion
C,O go from singly bonded to doubly bonded: they move closer to each other
OLi O C,C go from doubly bonded to singy bonded: they move + α E , γ-C away from each other greater extent of atomic motion: C,C go from singly bonded reaction disfavored γ to doubly bonded: they move E closer to each other C,C go from doubly bonded to singy bonded: they move away from each other
Kinetic protonation of dienolates: formation of deconjugated carbonyl compounds, e.g.:
O LDA O–Li H+ O OEt OEt OEt conjugated ester deconjugated ester CHEM 330 p.53
likewise:
O O–Li O H+
conjugated ketone deconjugated ketone
Difficulties encountered in the regioselective deprotonation of ketones such as 3- substituted cyclohexanones, e.g.:
O O O base + poor or no regioselectivity
Regioselective formation of enolates through dissolving metal (Li, Na, or K in liquid NH3) reduction of enones (= α,β-unsaturated ketones):
O O–Li Li 100% regioselective NH3 (liq)
OH
Nature of a solution of Li (or Na, or K) in liquid NH3: dissociation of the metal into a metal ion and an electron (both solvated), e.g.:
NH3 (liq.) Li Li Li + e (solid) (solution) (solvated) (solvated)
Powerful reducing properties of a solution of Li (or Na, or K) in liquid NH3 (≈ a solution of electrons)
Mechanistic aspects of the dissolving metal reduction of enones
• Radical anions and dianions
• Use of a proton donor such as tBuOH to accelerate the protonation of a (presumed) dianion intermediate formed during dissolving metal reductions of enones
C- and O- reactivity of the enolates thus obtained:
CHEM 330 p.54
Br
O–TMS O–Li O TMS-Cl
100% regioselective 100% regioselective
Principle: the alkylation of cyclohexanone enolates is especially important in the synthesis of compounds of current biomedical interest. Therefore, we need to explore the stereochemical aspects of this process in detail.
Stereochemical aspects of the alkylation of ketone enolates, e.g.:
H H H H R LDA R Me R Me and / or then O MeI O O O O–Li O O Li Br H H NH 3 (liq) Ph Ph and / or R OH R R R H H
Problem: is the alkylation step going to be diastereoselective? If so, which isomer will be the major product of the reaction?
Principle: stereochemical aspects of the alkylation of cyclohexanone enolates may be understood starting with an analysis of the stereochemical preferences of simpler, conformationally constrained cyclohexanones.
4-tert-Bu-cyclohexanone as a simple conformationally constrained cyclohexanone:
conformational constraint: t-Bu group stays equatorial and locks the ring in a specific conformation O too energetic: A tBu > 4.5 H val kcal/mol O H O
Principle: the alkylation of an enolate with an alkyl halide is irreversible, therefore, the reaction occurs under kinetic control. This means that the major product of the reaction will be the one obtained through the least energetic transition state.
CHEM 330 p.55
Possible sterochemical outcome of the alkylation of the enolate of 4-tert-Bu- cyclohexanone with, e.g., MeI: diastereomeric products will result depending on whether the enolate reacts with the electrophile from the top – or from the bottom face:
H MeI - MeI - H H bottom top OLi O face face O H H H Me attack attack Me trans diastereomer cis diastereomer
Pyramidalization of the nucleophilic sp2 C atom of an enolate as it rehybridizes to an sp3 state during alkylation
Approximate transition states for the alkylation of the enolate of 4-tert-Bu-cyclohexanone from the top or the bottom face of the π system:
E E
H H OLi OLi Top-face attack (as drawn): H H causing the ring to evolve the nucleophilic C-atom toward a twist-boat-like pyramidalizes upward .... conformer during the process that forms the new C - E bond: disfavored
E The E group is equatorial. conformational One may say that this is the H product of equatorial alkylation E O change (fast) of the enolate. Clearly, equatorial O H alkylation is disfavored on H kinetic grounds, because it the C - E bond is now fully (cis product) proceeds through a more formed: the ring is in a twist-boat energetic transition state conformation: disfavored
H H OLi OLi Bottom-face attack H E (as drawn): H E causing the ring to evolve the nucleophilic C-atom toward a chair-like pyramidalizes downward .... conformer during the C - E bond-forming process: favored
CHEM 330 p.56
The ring is stable as it is and it undergoes no further conformational change. The E group is axial. One H may say that this is the product of axial alkylation O of the enolate. It is apparent that axial alkylation is E favored on kinetic grounds, because it proceeds the C - E bond is now fully through a less energetic transition state. formed: the ring is in a chair conformation: favored (trans product)
Reaction diagram for the alkylation of a conformationally rigid cyclohexanone enolate:
twist-boat-like E
energy H OLi H chair-like more H energetic TS ΔE trans. sts. OLi H E less energetic TS
H more E energetic OLi ΔE prods. product H less energetic H product O E E O H react. coord.
Because the reaction is irreversible, the product distribution will be determined solely by the relative energies of the transition states; i.e., the major product will be the one that forms through the least energetic transition state. Such a fact may be expressed by saying that the reaction proceeds under conditions of kinetic control
Principle: the alkylation of conformationally rigid cyclohexanone enolates tends to occur so that the pyramidalization of the nucleophilic C atom of the enolate (i.e., the transition from a planar sp2 hybrid to a tetrahedral sp3 hybrid) causes the ring to evolve toward a chair conformer. This is the same as saying that alkylation of cyclohexanone enolates tends to occur in the axial mode.
Isomerization of the kinetic (axial) product of C-alkylation of an enolate to the thermodynamic (equatorial) isomer upon treatment with a catalytic amount of weak base that induces reversible enolate formation, e.g., MeONa / MeOH:
CHEM 330 p.57
cat. NaOMe Me axial (favored) ONa H MeOH protonation Me O H H–OMe O Me H axial Me: equatorial Me: thermodynamic enolate more energetic less energetic
Decalone: a ketone based on the decalin framework, e.g.:
2 1 O decalin O (cis or trans) 1-decalone 2-decalone
Similarity between trans-2-decalone and the A-B ring system of most steroids
Me R Z = H, Me Z could be Me H –OH or =O H H O (O) H H
Alkylation of enolates of trans-2-decalones as an issue of special relevance in the synthesis of steroids and other bioactive substances of current interest
Analogy between 2-decalones and 3-alkylcyclohexanones and potential difficulties encountered during their attempted conversion into regiochemically defined enolates by direct deprotonation
Dissolving metal reduction of conjugated 2-decalones as a means to access regiochemically defined enolates; e.g.:
Li, NH3 (liq)
O tert-BuOH LiO
Selective formation of a trans-decalin framework during protonation of the (presumed) dianion intermediate in the dissolving metal reduction of unsaturated decalones:
X X Li, NH 3 (l) presumed dianion intermediate - may exist as two conformers: O tBuOH LiO X = H or Me CHEM 330 p.58
X X ΔE > 2
LiO LiO kcal/mol H–OtBu cis-decalin-like trans-decalin-like less stable more stable minor conformer major conformer
X X enolate diastereomer formed (very) selectively LiO LiO H H
Trans-decalones as conformationally fixed cyclohexanones
Axial alkylation preference in the reaction of enolates of trans-decalones in which the X substituent at the ring junction is an H atom:
H H H E E (e.g, MeI)
O O O H H H H H E
Stereochemical aspects of the dissolving metal reduction / alkylation of decalone-based enones of interest in the synthesis of steroids:
(steroid) H H 1. Li, NH3 (l) the reaction creates 2 H H new stereogenic C's: tBuOH * diastereoselectivity ? O O * 2. E+ H E
Axial alkylation preference in the reaction of enolates of trans-decalones in which the substituent Z at the ring junction is an H atom:
Z H H H Li, NH3 (l) MeI Me
tert-BuOH (e.g.) O O O H H O H H Me H [ Z = H ]
likewise:
H H H E H E (e.g, MeI) E H O O O H H H CHEM 330 p.59
Syn-pentane interaction: a very energetic conformational interaction in a molecule of pentane possessing the following conformation:
syn-pentane interaction Me H H Me H H H H Me Me H H H H H H syn-pentane: ca. + 5 kcal/mol anti-pentane: most relative to anti pentane favorable conformer
Problems with the axial alkylation of enolates of trans-decalones where substituent Z at the ring junction is an alkyl group: a developing syn-pentane interaction between the incoming electrophile and the alkyl substituent promotes equatorial alkylation:
Z Me Me Li, NH3 (l) E
tert-BuOH O O O H H H [ Z = Me ] full syn- developing pentane E syn-pentane interaction interaction Me normally E Me Me favored E
mode of O O H O H alkylation H chair -like H H H trans. state
the energy required to overcome the developing syn-pentane interaction is greater than the energy required to cause alkylation through a twist-boat conformation !! Therefore, the alkylation occurs via:
twist-boat -like trans. state Me normally Me Me disfavored O O mode of H alkylation O H H H H H E E E twist-boat conformation Me Me H ring
flip O O E E H H H actual product
CHEM 330 p.60
H Me Me E E (e.g, MeI) Likewise: O O H H
Principle: when rationalizing / predicting the reactivity of more structurally complex cyclohexanone enolates (such as decalone enolates), one must evaluate not only the conformational preferences of the 6-membered ring (i.e., the preferential evolution toward a chair-like conformer during the alkylation step), but also the possibility / extent of other steric interactions. The major product of the reaction (at least initially) will still be the one obtained through the least energetic transition state.
Application of the above principles to a key step in the synthesis of nakijiquinone
O O Li / NH3 O O tBuOH H O HO OMe H O MeO MeO CH2Br O O MeO OMe OH OMe HN OMe OMe COOH nakijiquinone
note: nakijiquinone is a natural product that inhibits a tyrosine kinase (= an enzyme that transfer a phosphoryl group from ATP to the phenolic OH of a tyrosine residue in an particular protein), which is overactive in various breast, ovary, and gastric cancers. Inhibitors of this kinase are useful probes of biological function and candidate anticancer drugs.
Conformationally mobile cyclohexanones: those carrying substituents characterized by a small A-value; for instance, small alkyls like Me, Et, ..., e.g.:
O Me
Principle: the 6-membered ring in the enolate of a conformationally mobile cyclohexanone may readily access either half-chair conformer, because the energy difference between the two is small. For instance:
ΔE ≈ 0.9 kcal/mol: the LiO H CH3 axial CH3 experiences H CH3 H H LiO Me only ONE 1,3--diaxial H LiO H (gauche -butane) interaction
CHEM 330 p.61
Consequence: the inherent preference for the axial mode of alkylation may manifest itself from either conformer, complicating the prediction of the stereochemical outcome of alkylation reactions.
The 6-membered ring will generally tend to evolve from a half-chair to a chair-like conformer during the alkylation reaction. However, a multitude of interactions (steric, conformational, etc.) will determine which half-chair conformer of the enolate is more likely to participate in the alkylation event
Alkylation of enolates of simple 3-substituted cyclohexanones leading selectively to trans products, e.g.:
Li, NH3 (liq) PhCH2Br
O R tBuOH LiO Me O Me CH2Ph (small alkyl, e.g., Me) because:
equatorial Me conformer of Br significant the enolate steric H interaction axial alkylation H R LiO from equatorial CH 3 LiO Me conformer CH H H 3 O Me of the enolate H H H H CH2Ph H disfavored
ΔE ≈ 0.9 kcal/mol ΔE > 0.9 kcal/mol (small) H H axial alkylation H CH3 CH3 from axial Me H H LiO H conformer of LiO insignificant O Me the enolate H steric H CH2Ph axial Me R interaction conformer of observed the enolate Br product favored
Conclusion: extrapolating from what was stated earlier regarding decalone enolates, the stereochemical outcome of the C-alkylation of a generic cyclohexanone enolate is controlled by:
(i) the innate preference for axial alkylation through a chair-like transition state; (ii) conformational factors, and (iii) the extent of steric interactions between the incoming electrophile and various molecular subunits.
CHEM 330 p.62
All such factors contribute to determining the overall energy of the transition states leading to the various possible products. The major product of the reaction (at least initially) will always be the one obtained through the least energetic transition state — so long as the reaction is strictly kinetically controlled.
The preparation of enones of the type shown below as a significant objective in contemporary synthetic organic chemistry:
Z
or Z = H, Me, etc. O O
1,5-Dicarbonyl compounds as precursors of the target cyclic systems:
3 2 4 5 O O 1 O
Principle: a 1,5-dicarbonyl compound of the above type may be advanced to the desired enone (also described as a conjugated carbonyl or an α,β-unsaturated ketone) by an aldol – dehydration sequence:
base
O O O O O O O OH A nucleophilic addition of a carbonyl enolate to the C=O group of a ketone or aldehyde: aldol reaction (extremely important rx.) the progress of A to B under base elimination basic conditions involves a O reaction O dehydration: overall, we have an OH "aldol - dehydration" sequence B
Principle: an aldol-dehydration sequence is best carried out with bases that deprotonate the 1,5-dicarbonyl substrate reversibly, e.g., an alkoxide (or even HO–)"
base (e.g. NaOEt
or even NaOH) O O O O O O O O non-productive EtO–H enolate formation CHEM 330 p.63
± H+ base – HO–
O O O OH OH isolable under certain conditions, but in the presence of base ....
The base-promoted cyclization (= aldol-dehydration) of 1,5-dicarbonyls as a general, extremely useful method for the construction of 6-membered rings
But: how to prepare 1,5-dicarbonyl systems?
CHEM 330 p.64
E. Conjugate Addition Chemistry
Conjugate addition (also called 1,4-addition) reactions: processes in which a nucleophile reacts with a conjugated carbonyl compound (of any kind) not at the C=O group ("1,2- addition"), but at the distal olefinic center:
Nu Nu Nu + H Nu + Nu H Nu O O Z Z O Z HO Z O Z Z = H, alkyl, OR, .... the red mechanism the black mechanism describes a conjugate describes a direct C=O (or 1,4) addition addition (or 1,2-addition)
Preparation of 1,5-dicarbonyls through the conjugate addition of a carbonyl enolate to an α,β-unsaturated carbonyl substrate: the Michael reaction:
H+ + O R O R O Z O R Z O Z O
Michael donor: a generic nucleophile, such as a carbonyl enolate, that shows a propensity to add in a 1,4-mode to a conjugated carbonyl substrate.
Michael acceptor: the conjugated carbonyl compound that undergoes 1,4-addition upon treatment with an appropriate nucleophile, e.g., an enolate.
Principle: at the present state of your knowledge, it is not easy to predict whether a given nucleophile will add to an enone (in general, to a conjugated carbonyl compound) in a 1,2 or a 1,4 mode. Therefore, in this class we shall rely on precedent. Intellectual constructs that allow one to formulate a priori predictions are beyond the scope of CHEM 330.
Concerning the scope of Michael additions with respect to the donor:
Enolates of carbonyl (ketone, ester, 1,3-dicarbonyl ....) and carbonyl-like (nitrile, nitro ...) compounds as generally effective Michael donors
Enolates of active methylene and related compounds ("stabilized enolates") as especially effective nucleophiles in Michael reactions
Concerning the scope of Michael additions with respect to the acceptor:
(i) Conjugated ketones, esters, nitriles, etc. generally undergo efficient Michael reaction with carbonyl enolates of all types (= unstabilized and stabilized)
CHEM 330 p.65
(ii) Conjugated aldehydes tend to react with non-stabilized carbonyl enolates in a 1,2- mode, i.e., they tend to participate in aldol, rather than Michael, reactions, with such nucleophiles: O O Li-O LDA H etc. H O O Li
(iii) however, conjugated aldehydes react in a Michael mode with stabilized enolates (anions of active methylene compounds and related substances):
O O O appropriate EWG + EWG Z Z bases H CHO Z = alkyl, OR, ... EWG = electron-withdrawing group ( CO-R, COOR, CN ...)
Application of Michael additions and aldol-dehydration sequences in the preparation of enones useful for the synthesis of steroids:
oxygen functionality R O O (may be O= or HO–) C D O O A B contributes (O) rings C and D Wieland-Miescher ketone: contributes rings A and B generic steroid
The Wieland-Miescher ketone as an exceedingly important intermediate for the synthesis of steroids, antibiotics, and other biomedically significant compounds.
Synthesis of the above enones by a combination of Michael and aldol-dehydration reactions:
O O O aldol - Michael + dehydr. O O O O O Wieland-Miescher ketone O O O aldol - Michael + dehydr. O O O O O
Frequent use of amine (such as Et3N, etc.) and especially amidine bases as promoters of Michael additions of active methylene compounds CHEM 330 p.66
R1 N 2 R a generic amidine: R groups N may be H or alkyl R3 R4
Diazabicycloundecene (DBU): a cyclic amidine with good proton affinity (pKa ≈ 14), but poor nucleophilicity, which is widely used to promote Michael additions of active methylene compounds to conjugated carbonyls.
N
N DBU
Annulation reaction: a process that forms a ring through a multistep sequence.
Robinson annulation: a technique for the construction of cyclic enones through a multistep sequence that involves a Michael addition followed by aldol-dehydration; e.g.:
O O O DBU NaOMe
O O O O O
O O O DBU NaOMe
O O O O O
Facile 1,4-addition of weakly basic species like cyanide ion (pKa ≈ 10), primary and secondary amines (pKa ≈ 10-12), enamines, sulfur nucleophiles (pKa ≈ 5-10) etc.:
NC EWG R–S R–SH EWG CN base R2 1 2 EWG R R 1 N 2 N R R H EWG = Electron- R2 EWG 1 N R EWG Withdrawing Group N R1 (carbonyl, CN, NO2, ...)
Importance of aldol-dehydration and conjugate addition reactions in contemporary synthetic organic and heterocyclic chemistry
The Knoevenagel reaction: and aldol-dehydration sequence that involves the union of an aldehyde (sometimes a ketone) with an active methylene compound under simultaneous catalysis by a weak base and a weak acid; e.g. NH4OAc: CHEM 330 p.67
1 heat, cat. 1 EWG R EWG EWG = carbonyl, R CHO + (+ H O) 2 CN, NO , etc. 2 NH OAc 2 EWG 4 EWG2
Knoevenagel products as powerful Michael acceptors, due to stabilization of incipient enolates by two EWG's
Widespread application of Knoevenagel products as building blocks for the synthesis of more complex carbon frameworks, including heterocyclic systems
The Hantzsch pyridine synthesis as a route to biomedically significant substances
2 R 2 R2–CHO 2 EWG EWG1 EWG1 EWG NH heat, cat. 3 3 3 O R R1 O R1 O H2N R NH4OAc A B
2 R2 R2 R 1 2 1 2 mix EWG1 EWG2 EWG EWG [ O ] EWG EWG A + B heat 1 3 R1 R3 R1 N R3 R N R O H2N H
Application: industrial synthesis of cerivastatin (formerly used cholesterol-lowering drug)
HO COONa OH Wittig F F P(O)(OEt) F 2 COOEt i-Pr i-Pr N N N EtOOC MeO MeO i-Pr i-Pr cerivastatin (baycol. lipobay) COOEt F F COOEt i-Pr Hantzsch i-Pr CHO O NH NH O 3 EtOOC EtOOC i-Pr i-Pr
Assembly of the pyridine segment of cerivastatin
CHEM 330 p.68
F F COOEt OAc COOEt NH2 + i-Pr i-Pr CHO O heat O
then
F COOEt i-Pr
O O NH3 i-Pr EtOOC EtOOC
i-Pr NH2
F F F COOEt COOEt COOEt + i-Pr ± H i-Pr i-Pr
O O NH EtOOC EtOOH C i-Pr 2 NH2 EtOOC NH2 i-Pr i-Pr F COOEt i-Pr [ O ]
N EtOOC i-Pr
Principle: much like the dissolving metal reductions explored earlier, 1,4-addition processes, such as Michael reactions, lead to the regioselective formation of carbonyl enolates. Under appropriate conditions, such enolates may be intercepted with suitable electrophiles, leading to the formation of valuable products:
E E EWG EWG EWG Nu : Nu Nu
Example of a reaction in which a transient enolate generated though 1,4-addition to a Michael acceptor participates in a subsequent aldol step: the Baylis-Hillman reaction
R O R OH R–CHO – Nu-H EWG EWG EWG EWG Nu : Nu Nu Baylis-Hillman product
CHEM 330 p.69
Key aspects of the Baylis-Hillman reaction:
• reversible 1,4-addition of a suitable nucleophile to CH2=CH–EWG
• aldol-type addition of the resultant enolate to the aldehyde
• proton transfer and elimination of the nucleophile from the adduct
DiAzaBiCycloOctane ("DABCO") as an effective nucleophile in the Baylis-Hillman reactions
N "DABCO" N
Mechanistic aspects of the Baylis-Hillman reaction catalyzed by DABCO
N "DABCO" N
• nucleophilic character of DABCO
• reversible 1,4-addition of DABCO to CH2=CH–Z
• aldol-type addition of the resultant enolate to the aldehyde
• proton transfer and elimination of DABCO from the adduct
Principle: an enolate generated regioselectively by an appropriate 1,4-addition process may be induced to participate in not only in aldol reactions (such as in the Baylis-Hillman reaction), but also in Claisen-Dieckmann, 1,2– and 1,4-addition, and C / O alkylation, etc., reactions
Cascade processes: chemical transformations during which an initial chemical reaction, e.g., a Michael addition, generates a reactive intermediate, such as an enolate, which subsequently participates in additional reactions, such as any permutation of further Michael processes, Claisen-Dieckmann, aldol, etc. reactions
Cascade reactions involving Claisen-Dieckmann steps:
Difficulties encountered in the preparation of substituted fused polycyclic aromatic structures (naphthtalenes and more complex analogs) by the traditional methods of aromatic chemistry (formation of isomers, multiple reactions, etc.)
Benzannulation reaction: an annulation reaction that builds a new benzene ring
Acetylenic carbonyls as reactive Michael acceptors:
O R Z = alkyl, OR, etc. Z
CHEM 330 p.70
Cumulenes: organic compounds incorporating a triatomic functionality of the type X=Y=Z (e.g., ketenes, azides, carbodiimides, etc.)
Allenes: cumulenes incorporating the motif C=C=C
Allenolates: very reactive enolates obtained by 1,4-addition to acetylenic Michael acceptors:
E+ Nu: Nu E O Nu Z E+ R C C C R O Z O R Z
Principle: allenolates are unavailable by deprotonation of a conjugated carbonyl of the type shown below, because of coplanarity of the C–H and C=O systems
Z R1 O base R1 Z C C C R2 H R2 O : B
Example of a benzannulation reaction initiated by a Michael addition to an acetylenic acceptor:
generic ring O substituents O CN NC CN OMe C OMe R R KCN R COOMe MeO OMe O OMe O O
CN CN + R COOMe R COOMe H3O
workup O O H H MeO OH CN R COOMe R COOMe OH OH subunit found in many bioactive substances
Cascade reactions involving multiple 1,4– and 1,2-carbonyl additions
Interest of the tremorgenic natural product, aflavinine, as a probe of neuronal function
CHEM 330 p.71
OH aflavinine N H Indole: a heterocyclic system that is widely found among natural products and that possesses the structure show below
indole N H
Frequent presence of the indole system in neurologicaly active compounds
Plausible synthetic precursor of aflavinine given that the indole unit may be created from an ester group:
OH OH EtOOC
N H
Retrosynthetic logic for aflavinine:
aflavinine OH OH EtOOC EtOOC O this double bond could be made by hypothetical intermediate aldol-dehydration required: the O functionalities chemistry . . . are in a 1,5 relationship
Functional Group Interconversion ("FGI"): the replacement of a functional group G in a synthetic target with another functional group, G', that (i) facilitates the construction of the molecule of interest, and that (ii) may be easily transformed back to G.
CHEM 330 p.72
FGI in the above intermediate enabling the creation of 1,5-di-CO systems through Michael reactions:
FGI
OH O O EtOOC EtOOC EtOOC O O O
this ester enolate may now result through a Michael reaction. The 1,5-di-C=O relationship between the two ketones again suggests a Michael reaction . . .
easily made from O methyl isopropyl ketone + LDA O (kinetic enolate) COOEt the greater electrophilicity of a ketone C=O vs. an ester C=O translates into a greater Michael reactivity of an enone relative to a conjugated ester. In the present case, the enone is also less sterically hindered
Principle: just like a ketone carbonyl is more reactive than an ester carbonyl in 1,2-addition reactions, so an α,β-unsaturated ketone is more reactive than an α,β-unsaturated ester in Michael reactions:
So . . .
O LDA Li-O add
THF -78 C O COOEt then H+
aflavinine O EtOOC OH
The issue of diastereoselectivity in the above transformation
CHEM 330 p.73
O i-Pr * * O O O EtOOC A EtOOC COOEt O B O C
* * * * O O EtOOC * EtOOC * OH D E
Principle: only the formation of C above comports significant stereochemical issues, because…
the formation of B proceeds without the creation of new stereogenic centers: no stereochemical issues at this stage;
the formation of C proceeds with the creation of two new stereogenic centers (red asterisks), which are retained in the final product: a significant stereochemical issue is present at this stage;
the formation of D also proceeds with the creation of two new stereogenic centers (blue asterisks, but these vanish upon dehydration to E: no stereochemical issues here.
The enolate of B is likely to advance to C through the conformation depicted below, because …
B is the enolate of a cyclohexanone, and it will tend to undergo Michael alkylation in the axial mode, so that its ring system may evolve directly toward a chair-like conformer;
the new ring is likely to form through a chair-like transition state;
the fact that the molecular segment containing the conjugate ester group is tethered to the enolate subunit will force the reaction to produce a cis-decalin-type product:
CHEM 330 p.74
H Me H Me H O Me O H H O COOEt H COOEt Me COOEt Me Me H H H B H H Me H Me Me O C O O
the cyclohexanone enolate undergoes Michael alkylation in the axial mode via chair- like transition state
The problem of conjugate addition of alkyl groups to Michael acceptors
Preferential 1,2-addition of Grignard and organolithium reagents to Michael acceptors
Desirability of a method to effect the conjugate addition of carbanions to Michael acceptors
Principle: the nature of the metal, Mt, bound to the carbanionic portion, R, of a generic organometallic agent, R–Mt, modulates the reactivity of the carbanion, rendering it more basic, or more nucleophilic, or more inclined to undergo 1,2-addition, or more inclined to undergo 1,4-addition.
Organocopper reagents as reactive agents in 1,4-additions to unsaturated carbonyls
Stable oxidation states of copper: Cu(I) and Cu(II)
Principle: only Cu(I) forms organometallic species that are stable enough to be used as reagents in synthetic operations
Preparation of organometallics by the "direct" method, e.g:
R–Br + Mg à R–MgBr R–Br + 2Li à R–Li + LiBr
Principle: the metal undergoes oxidation during formation of an organometallic reagent
Limited scope of the direct method, which works substantially only with metals that are readily oxidized (Li, Mg, Zn, Al ...)
High oxidation potential of Cu(0) and consequent inaccessibility of organocopper agents by the direct method
Transmetallation reaction: exchange of the carbanionic portion between an organometallic agent, R-Mt1, and the salt of a second metal, typically a halide Mt2X (X = Cl, Br, I): CHEM 330 p.75
R–Mt1 + Mt2–X R–Mt2 + Mt1–X
Principle: transmetallation equilibria are strongly shifted toward the organometallic agent containing a more covalent C–Mt bond; i.e., toward the organometallic agent containing the more electronegative metal
Preparation of organocopper reagents by transmetallation, e.g.:
this reaction will favor the product containing the R–Li ≈ R Li Cu(I)–Br R–Cu(I) more covalent C-Mt bond. Cu is more e.n. than (gross oversimplification: R-Li is not ionic, Li, so the C-Cu bond is more covalent than the C-Li bond. The equilibrium is shifted to the right. though the C-Li bond is polarized)
Mono-alkylcopper (I) agents: organometallics of formula R–Cu prepared from 1 mol of R-Li by a transmetallation reaction with 1 mol of Cu(I) halide:
R–Li ≈ R Li Cu(I)–Br R–Cu(I) + LiBr
Poor solubility and relative inertness of R–Cu(I) agents
– + Lithium dialkyl cuprates: copper(I) organometallics of general formula R2Cu Li prepared by reaction of 1 mol of Cu(I) halide plus two mols of R-Li, as follows:
R Li R–Li ≈ R Li Cu(I)–Br R–Cu(I) R–Cu–R Li
Ate complexes: organometallics in which the metal carries a formal negative charge (e.g., borates, aluminates, zincates, cuprates, …) Highly reactive nature of dialkyl cuprates
Note: the process leading to formation of a cuprate is not an oxidative addition, because the oxidation state of the metal remains unaltered during the reaction:
2 MeLi + CuI Me2Cu Li not an oxidative addition: Cu stays as Cu(I) throughout [Cu(I)] [Cu(I)]
Strong tendency of the R "carbanion" carried by a cuprate to add in a 1,4 mode to conjugated carbonyls and related species:
CHEM 330 p.76
O
+ H3O R O O an enolate: it undergoes TMS-Cl O–TMS Li all reactions typical of R enolates, e.g.: R R–Cu–R Li Me-I O (gross oversimplification of + R–Cu(I) the reaction mechanism) (inert) R Me
Poor reactivity of enolates generated regioselectively through cuprate 1,4-additions due to their association with R–Cu(I).
Metal-chelating properties of tetramethylethylenediamine (TMEDA)
Me2N-CH2-CH2-NMe2
Coordination of the monoalkyl-Cu(I) residue with amine ligands (e.g, TMEDA, or even Et3N) as a method to "liberate" the enolate and cause it to react normally with electrophilic agents, e.g.:
TMEDA O-SiMe3
O O-Li • Cu-Me TMS-Cl Me2CuLi O
TMEDA Ph
relatively unreactive PhCH2Br
Poor reactivity of organolithium or organomagnesium (Grignard) reagents in SN2 reactions
Cuprates as carriers of very nucleophilic (= high carbon affinity), but weakly basic (poor proton affinity), "carbanions" that are highly reactive in SN2 reaction, e.g.: X Me Me2CuLi
fast, clean X = Br, I, OTs
High reactivity of organolithium or Grignard reagents in nucleophilic 1,2-addition to carbonyls.
Poor reactivity of cuprates in nucleophilic 1,2-addition to carbonyls
Ability of cuprates to convert acid chlorides into ketones (difficult / impossible to do with R-Li or R-MgX reagents) as a consequence of poor reactivity in 1,2-C=O addition:
CHEM 330 p.77
O Me CuLi O the cuprate is a poor nucleophile in 2 1,2-additions to ketones: the reaction R Cl R stops at the stage of the ketone
Principle: cuprates are the reagents of choice in 1,4-additions and in SN2 reactions; organolithiums and Grignards are the reagents of choice in carbonyl 1,2-addition reactions.
Principle: a dialkyl cuprate (e.g., lithium dimethyl cuprate) transfers only one of its two alkyl groups, because of the poor reactivity of simple monoalkyl copper(I) species
Trigonal bipyramidal structure of a cuprate ion when the 3 high-energy lone pairs around the Cu atom are taken into account:
R
lone pairs Cu
R Li
Principle: various aspects of the mechanisms of organocuprate reactions remain controversial. However, it is likely that a key step involves the expression of nucleophilic character by the negatively charged Cu atom through one of its three energetic lone pairs:
O R O O R (III) (I) Cu Li Cu R R R + R–Cu(I) cuprate: Cu bound to 3 C and w/ no formal charge: Cu(III). (inert) Cu(I) Cu(III) is a strong oxidant: this complex undergoes "extrusion" of a reduced form of the metal through a process that results in ligand coupling:
Oxidative addition: a process involving formation of a metal-C bond and proceeding with concomitant 2-electron oxidation of the metal, e.g.:
O Me Me Li oxidative addition, Li O Cu Cu because Cu goes from Cu(I) to Cu(III) Me Me [Cu(I)] [Cu(III)]
Reductive elimination: a process involving the decomposition of an organometallic reagent, normally proceeding with ligand coupling, during which the metal undergoes a 2-electron reduction, e.g.: CHEM 330 p.78
Me + Me-Cu Cu O Me O Li Me Li [Cu(I)] [Cu(III)]
Principle: only syn-disposed ligands can undergo coupling during reductive elimination: O Z R (III) O Cu Z Li R R + R–Cu(I) (inert) Coupling is only possible only between R and the "enolate." We take the liberty to shown the mechanism as depicted. No R-R coupling may occur (the metal is "in the way")
Possible mechanism of SN2 reactions with cuprates:
Me H Li Me X oxidative reductive Me Cu Cu + Me-Cu R R' addition R elimination R R' Me Me R' [Cu(III)] [Cu(I)] [Cu(I)] X = Br, I, OTs
Principle: the same effects that govern the stereochemical course of the alkylation of cyclohexanone enolates also control the stereochemical course of 1,4-addition of cuprates to cyclohexenones:
i. Preferential axial attack in conformationally rigid cyclohexenones (chair-like TS's)
H H Me Me2CuLi H + then H3O O H Me O O
ii. Preferential attack anti to small alkyls in conformationally flexible cyclohexenones
H Me Me2CuLi Me
+ O then H3O O Me H
Application of cuprate technology in the chemical synthesis of biologically relevant substances: prostaglandins (important hormones):
CHEM 330 p.79
O O COOH 1,4-addition
C5H11-n HO Si O C5H11-n OH tert-butyl- O Si dimethylsilyl a prostaglandin: PGE2 directs the prot. group cuprate to (from a cuprate) the anti face
should enter anti relative I to neighboring alkyl group O O
COOMe SN2 COOMe C H -n C5H11-n 5 11 TBSO TBSO OTBS OTBS TBS: shorthand for "tert-butyl-dimethylsilyl"
Reminder: a dialkyl cuprate (e.g., lithium dimethyl cuprate) transfers only one of its two alkyl groups, because of the poor reactivity of simple monoalkyl copper(I) species
Problem: implementation of the above strategy requires a cuprate in which two vinyl "carbanions" are bound to the metal, but only one of them is usable. This is wasteful, because the carbanionic segment is itself the product of chemical synthesis.
Mixed cuprates: organometallic agents of formula R1–Cu(–)–R2 Mt+ (Mt = Li, MgBr, etc.) that are prepared as shown below; e.g.:
R2–Li R1–Li + CuBr R1–Cu R1–Cu–R2 Li insoluble soluble
Relative rate of transfer of alkyl groups connected to the Cu atom in a cuprate: sp2 alkyls (vinyls, phenyls, etc.) > sp3 alkyls (Me, Et, etc.) >> sp alkyls (acetylides)
Methods to suppress the wasteful loss of one of the two alkyl ligands of a cuprate:
• Use of a mixed cuprate carrying a non-transferable "dummy ligand" such as an acetylide (no longer popular these days because of safety issues associated with Cu(I) acetylides): CHEM 330 p.80
only R is transferable CuI, R-Li n-C3H7 H n-C3H7 Cu n-C3H7 Cu R base 1-pentyne: a (relatively inert) Li cheap alkyne "dummy ligand" doesn't transfer
• Use of cyanocuprates (widely used in modern synthetic technology):
R–Li Cu–CN N C Cu–R Li only R is transferable
• Use of Noyori organocopper agents (widely used; note: these are not "cuprates", because they are not "ate" complexes).
2 PBu X = Br, I insoluble 3 R-Li CuX (Bu P) CuX (Bu P) Cu R (+ LiX ) in organic solvents 3 2 3 2 soluble in org. solvs. only R is transferable
Preparation of organometallics by the halogen-metal exchange reaction, e.g.:
X BuLi Li X = Br, I (+ BuX) R R
Driving force for the halogen-metal exchange reaction: decrease in the basicity of the system (pKa BuLi ≥ 50; pKa vinyl-Li ≈ 40) and consequent decrease in free energy
Greater reactivity of tert-BuLi relative to n-BuLi in halogen-metal exchange reactions:
X Li X = Br, I + Li R R
tert-butyllithium (tBuLi)
Scope of the halogen-metal exchange reaction:
Li X Li Li X tBuLi R R "tert-butyllithium" X = Br, I X = Br, I or tBuLi
tBuLi R CH -Li R CH2-I 2 (substantially limited to primary iodides)
Prostaglandin synthesis via organocopper technology (Noyori – 1985): CHEM 330 p.81
tert-BuLi (Bu3P)2CuI I C5H11-n Li C5H11-n
OTBS OTBS
O O Li • Cu(PBu3)2
(Bu3P)2Cu C5H11-n + C H -n OTBS 5 11 TBSO TBSO OTBS
O I COOMe COOMe PGE2 C H -n 5 11 appropriate TBSO conditions OTBS
CHEM 330 p.82
F. Construction of β-Hydroxycarbonyl Assemblies
The problem of assembling 1,3-hydroxycarbonyl compounds by an aldol reaction of an achiral aldehyde with an achiral enolate:
OH O O O
R1 R3 R1 R3 2 R2 R achiral achiral
Syn and anti aldol diastereomers:
OH both up OH O OH O 2 H R O H or O 1 3 1 3 R R R R 1 1 R H R3 R 3 R2 R2 OH R H 2 syn diastereomer R both down
because in either molecule OH and R2 molecular plane defined by the main chain in an extended conformation groups reside on the same face of the plane defined by the main chain of the molecule in an extended conformation one up, one down OH OH O OH O H H O R2 or O 1 3 1 3 R R R R 1 1 R H R3 R 3 R2 R2 OH R R2 anti diastereomer H because in either molecule OH and R2 molecular plane defined by the main chain in an extended conformation groups reside on opposite faces of the plane defined by the main chain of the molecule in an extended conformation
Reminder: enatiomers have identical thermodynamic properties diastereomers have distinct thermodynamic properties
Principle: it is not going to be possible to achieve selective formation of a particular enantiomer of the product during the foregoing aldol reaction, because the thermodynamic properties of two enantiomers are identical, but it may be possible to achieve selective formation of a particular diastereomer of the product (syn or anti), because the thermodynamic properties of two diastereomers differ.
The aldol reaction as a potentially diastereoselective, but not enantioselective, process
Principle: good diastereoselectivity in aldol reactions is often observed if:
CHEM 330 p.83
(i) the process occurs under kinetic control (= conditions of irreversibility), and
(ii) the carbonyl enolate contains a strongly oxophilic metal
Oxophilic metals: small ions with a strong charge density and orbitals that interact readily with the orbitals of oxygen, e.g.: Li, B, Mg, Al, Zn, Ti, Zr….
Existence of metal enolates as two possible geometric isomers: E and Z enolates
O Mt O Mt E and Z metal enolates are H R2 stereochemically stable, i.e., R3 R3 they do not interconvert under R2 H ordinary conditions, especially E - enolate: O-Mt Z - enolate: O-Mt if Mt is strongly oxophilic and R2 are trans and R2 are cis
Mechanistic picture for a kinetically controlled aldol reaction of an achiral enolate containing an oxophilic metal with an achiral aldehyde:
First interaction between an aldehyde and an enolate containing an oxophilic metal: Mt – O complex formation
Selective formation of the trans-type complex for steric reasons
e.g., with an E-enolate:
Mt Mt O first O O O (the same holds true 3 interaction 1 3 for a Z enolate) R1 H R R H R R2 R2 generic E enolate trans - complex
Increased electrophilicity of the aldehyde and increased nucleophilicity of the enolate as a consequence of complex formation:
Mt The enolate is more The C=O is more O O electrophilic, due to nucleophilic due to the formal (–) on Mt the formal (+) on O R1 H R3 R2
"Double activation" of the aldehyde-enolate complex toward C–C bond formation due to increased electrophilicity of the aldehyde and increased nucleophilicity of the enolate CHEM 330 p.84
Evolution of the aldehyde-enolate complex toward a chair-like conformer that juxtaposes nucleophilic and electrophilic carbons for C-C bond formation, and in which as many groups as possible are pseudoequatorial
Existence of two enantiomeric variants of the conformation (transition state model) that permits C-C bond formation:
3 R3 R H H Mt R2 R2 O O 1 R1 R R1 H R3 Mt Mt O O O O 2 R b H a H a and b are enantiomeric structures. In red; incipient C–C bond. Notice that 1 2 substituents R and R occupy equatorial positions in these chair-like constructs
note: the coordination sphere of the metal is completed by an appropriate number of solvent molecules
Principle: the enolate-aldehyde complex will partition equally between the two enantiomeric conformers (transition states) a and b above, because a and b possess identical thermodynamic properties
C–C bond formation from structures a and b though a pericyclic mechanism (one involving a cyclic movement of electrons):
R3 H H R3 R2 R2 mild OH O 1 1 R R R1 R3 Mt Mt H O+ O O O O 3 R2 a H H a metal alkoxide: initial enantiomeric forms of product of the aldol rx. the anti diastereomer 3 H R 2 H 3 R R2 R mild OH O
1 1 3 R R1 + R R Mt Mt H3O O O O O R2 b H H
Selective formation of the racemate of the anti diastereomer of the aldol product in the reaction between an aldehyde and an E-enolate containing a strongly oxophilic metal such as Li+
Selective formation of the racemate of the syn diastereomer of the aldol product in the reaction between an aldehyde and a Z-enolate containing a strongly oxophilic metal such as Li+, e.g.:
CHEM 330 p.85
3 R3 H H R H Mt H O O 1 R2 R R1 Mt R1 H R3 Mt O O O O aldehyde - Z-enolate complex a R2 b R2 notice that only R1 can be equatorial H H in transition state structures a and b R3 R3 H H metal alkoxides: initial R1 R1 products of the aldol rx. Mt Mt O O O O R2 2 R OH O OH O mild mild R1 R3 R1 R3 + H O+ H3O R2 R2 3 enantiomeric forms of the syn diastereomer
Diastereoselectivity of the aldol reaction between aldehydes and enolates containing strongly oxophilic metals:
E-enolate à anti aldol product Z-enolate à syn aldol product Description of the above mechanistic picture as the Zimmermann-Traxler model for the aldol reaction
Tighly bound (closed, highly associated) transition state: one during which reacting molecules are tightly held together by non-covalent interactions that take place prior to the main bond reorganization event.
Examples of reactions that proceed via a tightly bound transition state: (i) Zimmermann-Traxler aldol reaction of enolates containing strongly oxophilic metals (ii) Deprotonation of carbonyl compounds with LDA
Principle: because enolate geometry determines which diastereomer of the aldol product is going to form, it is essential to be able to create E and Z enolates diastereoselectively from any carbonyl compound.
Tetrahydrofuran (THF): an ether solvent commonly used in enolate chemistry and in many other organic reactions
O tetrahydrofuran
Ester enolates: stereoselective preparation of E enolates by deprotonation with LDA in THF, e.g.:
CHEM 330 p.86
O–Li O LDA, –78°C THF OEt OEt
Mechanistic model for E-enolate formation:
Me group is equatorial OEt S Li S S Me N Solvent H Li O O N Li (THF) O N OEt EtO S H OEt S Me H E-enolate coordinated Li O N to diisopropylamine S H
Preparation of Z ester enolates by deprotonation with LDA in THF/HMPA (the Ireland method), e.g.:
O LDA, –78°C O–Li OEt THF / HMPA OEt
Conformational preferences of acyclic carbonyl compounds:
(i) Dunitz-Bürgi angle: the angle of ca. 100° between the axes of the large lobes of a π*C=O orbital and axis of the σ C=O bond:
Dunitz-Bürgi angle: α ≈ 100° R1 R2 C O π*C=O Dunitz-Bürgi angle: α ≈ 100°
(ii) preference for a syn (eclipsed) conformation in carbonyl compounds probably due to hyperconjugation:
θ ≈ 20° 2 H H cos θ ≈ 0.9 --> good σ C–H Me hyperconjugative dihedral angle O Me delocalization of σC–H Me–C–C–O ≈ 0 : EtO R C O syn conformer electrons into the H π*C=O π*C=O orbital σ C–H H
whereas, e.g.:
CHEM 330 p.87
θ ≈ 40° H 2 dihedral angle cos θ ≈ 0.6 --> Me 30% less Me–C–C–O ≈ 180 : R C O anticonformer hyperconjugative stabilizalization H
(ii) possible formation of Z enolates by deprotonation of an ester under conditions that do not perturb the innate conformational preferences of the substrate
(iii) one must effect deprotonation through a mechanism that involves no preliminary interaction between reagent and substrate. This may be achieved by coordinating the Li ion with a ligand so powerful that the ester C=O group will be unable to displace it from the metal.
Reminder: HMPA (HexaMethylPhosphorAmide) as a polar, aprotic, strongly Lewis basic solvent that – unfortunately – is quite hazardous.
O P Me2N NMe2 NMe2 (iv) strong coordination Li-HMPA
P (shorthand for HMPA) P O Li P O O N Li repeat O N Li P O N Me2N NMe2 2 X P NMe2
(v) suppression of Lewis acid-base interactions between Li ligated by HMPA and carbonyl oxygen P P P O P O HMPA is such a strong O O Li Li ligand for Li that the C=O N R N oxygen cannot displace it: O O O P EtO EtO R
(vi) deprotonation through a non-associated transition state (no preliminary interaction between reagent and substrate before bond reorganization):
S S Li N N S O–Li H S Me Me S Li H S OEt Me H O H EtO O Z - enolate EtO H
CHEM 330 p.88
Summary: stereoselective preparation of ester enolates and their aldol reaction:
O–Li LDA, –78°C O LDA, –78°C O–Li
OEt THF OEt THF / HMPA OEt E-enolate Z-enolate
R–CHO R–CHO OH O (both racemic) OH O R OEt R OEt anti syn
Description of non-associated transition states, such as the one postulated for the Ireland deprotonation of esters, as a "non-associated" or "extended" or "open" or "Yamamoto- type" transition states.
Principle: good stereoslectivity is often observed in organic reactions that proceed through either a strongly associated (= Zimmermann-Traxler-type) or a non-associated (= Yamamoto-type) transition state. Weak stereoselectivity may result if reactions proceed through weakly associated (= neither Zimmermann-Traxler-type nor Yamamoto-type) transition states.
Aldol reactions of ketones: stereoselective preparation of boron enolates by the Paterson method
9-Borabicyclononane (9-BBN) and 9-BBN triflate:
H OTf OTf 9-BBN: H B 9-BBN triflate: B a special abbreviated B B hydroboration as: obtained from 9-BBN +TfOH reagent
Stereoselective preparation of Z ketone enolates with 9-BBN-OTf and Hünig base, e.g:
9-BBN-OTf B O O
Ph (i-Pr)2NEt (Hünig base) Ph
Plausible mechanism for Z-enolate formation: stereoselectivity controlled by the conformational preferences of the ketone:
CHEM 330 p.89
highly oxophilic OTf TfO B TfO B B B O O O O Ph Ph Ph Ph Z enolate Et3N H these protons are preferred conformation now unusally acidic
Dicyclohexyl boron chloride (= dicyclohexyl chloroborane):
abbreviated as Cy2BCl B Cl
Stereoselective preparation of E ketone enolates by reaction with dicyclohexylboron chloride and Et3N, e.g.:
Cy Cy2BCl B O O Cy Ph Et3N Ph
Plausible mechanism for E enolate formation: stereoselectivity controlled by steric interactions between the cyclohexyl groups and the alkyl groups connected to the ketone carbonyl:
Cl Cl B B B O O O Cl Ph Ph Ph serious steric serious steric preferred conformation interactions interactions
Cy B O Cy B E enolate O Ph Et N H 3 Ph diminished interaction: more stable conformer
Aldol reaction of a Paterson (Z)-enolate of diethylketone through a Zimmermann-Traxler type mechanism:
CHEM 330 p.90
Me B OH O O 1. R–CHO R O syn-diasteroemer H R Ph (racemic) Ph + O 2. Mild H3O B Z enolate Et H
Aldol reaction of a Paterson (E)-enolate of diethylketone with, e.g., benzaldehyde through a Zimmermann-Traxler –type mechanism:
Cy H OH O B 1. R–CHO R O Cy O anti-diasteroemer Me R Ph (racemic) + O Ph 2. Mild H3O B Ph H E enolate
Preparation of enolates of tertiary amides
reminder; primary and secondary amides undergo preferential N-deprotonation (pKa of N–H group ≈ 16), and the resulting anion resists further deprotonation at the carbonyl α-position
A1,3-interaction in allylic systems:
Me R Me groups R and Me are strongly compressed against each other: Me R Me they are said to experience an allylic-1,3 (= A1,3) interaction favorable unfavorable conformation conformation
A1,3-like interaction in the conformer of a tertiary amide that would lead to an E-enolate:
O O O Me Me R Me R N N N A1,3-type interaction: Me R Me favorable Me very unfavorable conformation
Deprotonation of tertiary amides: selective formation of Z-enolates controlled by steric and conformational effects:
O O–Li OH O LDA 1. R–CHO R NMe2 N N + THF 2. Mild H3O Z-enolate syn-diasteroemer ONLY (racemic)
CHEM 330 p.91
Aldol reactions of aldehyde enolates: as a consequence of the difficulties encountered in the deprotonation of aldehydes with, e.g., LDA (rate of deprotonation ≈ rate of aldol addition of the enolate to an intact aldehyde and consequent polymerization of the aldeyde under basic conditions), aldehydes are unsuitable for the conduct of stereocontrolled aldol reactions of the type seen in CHEM 330 (kinetic control, etc.).
note: lithiated imines, hydrazones, etc. are also generally not useful for the conduct of stereocontrolled aldol reactions
Aldol reactions of aldehydes as processes of industrial significance but of limited scope Principle: industrially important aldol reactions are generally carried out by converting the aldehyde partially and reversibly to the enolate with a weak base, and by intercepting the enolate with appropriate electrophiles in situ.
Applications: synthesis of polyols (= poly-alcohols), such as pentaerythritol (structure below), of interest as components of polyester resins used in paints and coatings, as well as in the manufacture of commercial explosives:
aq. Ca(OH)2 HO OH CH3–CHO H2C=O HO OH
Mechanism for the formation of pentaerythritol:
OH H O CHO H CHO 2 CH2 CHO CH2 CHO H O OH O H repeat
OH OH repeat HO OH then . . . HO CHO CHO HO OH OH OH
Mechanism for the formation of pentaerythritol:
HO ? HO OH HO CHO HO HO OH
The Cannizzaro reaction: disproportionation of non-enolizable aldehydes, such as HCHO or PhCHO, upon reaction with, e.g., NaOH:
CHEM 330 p.92
+ O NaOH O H3O O 2 G G–CH2–OH + G G H ONa OH G = H: formaldehyde G = Ph: benzaldehyde (non enolizable aldehydes)
Key step in the mechanism of the Cannizzaro reaction: hydride transfer from a gem- diolate anion to an intact aldehyde:
OH H HO O H O H O O O etc. H H H H H O CH3
Biological significance of the Cannizzaro reaction: destruction of certain toxic aldehydes formed as metabolic byproducts and implicated, e.g., in the onset of type I diabetes
The problem of absolute stereocontrol in aldol reactions
Principle: the configuration, R or S, of a stereogenic center formed upon the addition of a nucleophile to an aldehyde depends on which face of the C=O group interacts with the incoming nucleophile:
same R-configuration molecule S-configuration OH OH O O Me Me Ph H H Ph
H3C H CH3 PhMgBr H PhMgBr
as shown in the above diagram, nucleophilic attack from one face of the C=O group produces one configuration of the newly formed stereogenic center; attack from the opposite face will produce the other configuration.
Si and Re stereochemical descriptors to distinguish the 2 faces of a carbonyl group:
CHEM 330 p.93
Cahn-Ingold-Prelog priorities (same as for R / S notation) plane of the C=O system same plane of the C=O system molecule a nucleophile approaching a nucleophile approaching from this side sees a CCW 1 1 from this side sees a CW arrangement of priorities: arrangement of priorities: O O this is the Si face of the this is the Re face of the carbonyl group carbonyl group Nu Nu H3C H H CH3 2 3 3 2
Notice: attack from the Re face does not necessarily lead to the R configuration of the newly formed stereogenic carbon. Likewise, attack from the Si face does not necessarily produce the S configuration. Which configuration is formed depends both on which face of the C=O reacts with the incoming Nu, and on the priorities of Nu and of the C=O substituents. Example:
same molecule S-configuration R-configuration 1 1 OH OH O O Ph Ph Me H H Me
Ph Ph MeMgBr H H MeMgBr 2 3 3 2 Re face attack Si face attack
In this case, nucleophilic attack from the Si face produces the S configuration of the newly formed stereogenic center; Re face attack produces the R configuration.
BUT:
same molecule R-configuration S-configuration 1 1 OH OH O O Me Me Ph H H Ph
H C CH PhMgBr 3 H H 3 PhMgBr 2 3 3 2 Re face attack Si face attack
In this case, nucleophilic attack from the Si face produces the R configuration of the newly formed stereogenic center; Re face attack produces the S configuration. CHEM 330 p.94
Principle: the transition states for the attack of an achiral nucleophile to either of the two faces of an achiral aldehyde are enantiomeric; therefore, they are thermodynamically equivalent. A reactive system comprising an achiral aldehyde + an achiral nucleophile will evolve with equal probability toward either of the 2 TS's, resulting in formation of a racemic product:
R–CHO + Nu
O O Nu OH HO Nu R H H R Nu Nu R H H R enantiomeric trans. states
enantiomeric products
Breaking the mirror-image symmetry of the two possible transition states of the aldol process by introducing chirality in the aldehyde (the substrate of the reaction), in the nucleophile (the reagent), or in both:
under such conditions, the above transition states become diastereomeric; i.e., thermodynamically inequivalent. Therefore, one of them may become more favorable than the other
Asymmetric synthesis: one in which newly created stereogenic centers form selectively with one configuration, the latter being determined by the stereochemical properties of the substrate, the reagent, or both
Substrate control (= chirality present in the aldehyde), reagent control (= chirality present in the enolate), double diastereocontrol (= chirality present in both aldehyde and enolate) in aldol reactions
Substrate control in nucleophilic additions to carbonyl groups: the case of aldehydes such as the one shown below, in which a stereogenic center at the α-position of (= closest to) the carbonyl group carries a small-size substituent (the H in the case of the Cram aldehyde), a medium-size substituent (Me) and a large-size substituent (the Ph group):
L CHO CHO M S Me H
Principle: a priori, the above aldehyde may react with a nucleophile, Nu, to form either of 2 diastereomeric products, depending on whether Nu attacks the Si or the Re face of the carbonyl group:
CHEM 330 p.95
HO H O Re-face Ph Ph attack: Nu CHO Me H diastereomers H Nu HO H H A Me H Ph Me Si-face Nu attack: Me H but because the transition states leading to the 2 products are themselves diastereomeric, they are thermodynamically non-equivalent, so, one of the two products may form diastereoselectively.
Description of the above aldehyde (phenylpropionaldehyde) as the Cram aldehyde
"Faciality" of a nucleophilic attack on a C=O group: description of which face, Si or Re, of the C=O system interacts preferentially with the incoming nucleophile on the basis of, e.g., the Cram-Felkin reactivity model
Principle: the facial preference of an aldehyde such as the Cram aldehyde during nucleophilic addition to the C=O group may be rationalized on the basis of steric effects
Reaction of the Cram aldehyde with a generic nucleophile: approach to the carbonyl group along a Dunitz-Bürgi trajectory:
Nu Dunitz - Bürgi angle ≈ 100° axis of the Nu orbital containing Note:!This diagram shows the electron pair and of the large a nucleophile attacking the lobe of the π*C=O orbital. These R2 C = O C=O from the top face. orbitals must be coaxial during O bond axis Identical considerations 1 apply for a C=O attack!from the nucleophilic attack on the C=O R plane of the bottom face the C = O system π*C=O orbital.
Conformational preferences of the Cram aldehyde with respect to internal rotation about the bond between the carbonyl C and the α-C:
Ph H Me good hyperconj. Ph O H σC–H – π*C=O O H H Me
O eclipsing smaller Me O eclipsing larger Ph group: less energetic group: more energetic more favorable less favorable
Behavior of the aldehyde in question during nucleophilic addition to the C=O system: preferential reaction from the Si-face according to the diagram shown below: CHEM 330 p.96
more favorable conformer
this conformation of the aldehyde directs the incoming nucleophile to attack from the Si face, because by doing so the Nu experiences Si-face Me the least steric interaction as it O H "grazes" past the substituent of attack smallest size (the H in this case) H Notice the Dunitz-Bürgi angle of steric attack (ca. 100° from the C=O axis) interaction Nu
Ph HO HO H H Nu Me H Me H Nu major product
Principle: the chirality present at the α-carbon of the C=O group promotes preferential reaction from a particular face of the C=O (the Si face in the present case)
Description of the rationale for the stereoselectivity observed in the reaction of the above aldehyde (only C / H α-substituents) as the Cram-Felkin reactivity model
Asymmetric syntheses employing aldehydes possessing a stereogenic center at the C=O α-position and generalization of the Cram-Felkin model:
• applicable to any aldehyde possessing ONLY C or H α-substituents at the α- position
• description of the α-substituents as the small (S), medium (M) and large (L) groups (as determined by their A-value). In the Cram aldehyde, the Ph (A-value ≈ 3) is L, the Me (A-value = 1.8) is M and the H is S.
• preferential reaction of such aldehydes from the favorable conformation depicted below, in which (i) a good hyperconjugative interaction subsists between S and the π*C=O orbital, (ii) the O atom eclipses the M substituent and (iii) the approaching nucleophile interacts with S:
L L M HO H O H product formed stereoselectively M S S Nu
Nu
CHEM 330 p.97
"Faciality" of a nucleophilic attack on a C=O group: description of which face, Si or Re, of the C=O system interacts preferentially with the incoming nucleophile on the basis of, e.g., the Cram-Felkin reactivity model
"Topology" of an aldol process: description of whether the reaction proceeds through a tightly bound, Zimmermann-Traxler transition state (or in accord with other reactivity models not covered in CHEM 330), and whether an E or a Z enolate is employed.
Stereochemical aspects of the aldol reaction of, e.g. the Cram aldehyde:
the abolute configuration of this center is determined by the faciality of the process; i.e., Cram-Felkin preferences of the substrate, which are controlled by the chirality of the C=O α-center
O R assuming a Zimmermann-Traxler Z OH O topology, the relative configuration CHO of these centers is determined by Z the enolate geometry (E / Z) Me H enolate from an ester, ketone, Me H R amide, etc.
Accordingly, the major product formed during the following representative reactions of E-enolates will be (after the usual aqueous workup):
O–BCy2 O–Li OH O H OH O OEt H CHO H OEt Me H Me H Me H Me H Me
Likewise, the major product expected (not necessarily obtained: more about this later…) during the following representative reactions of Z-enolates will be (after the usual aqueous workup):
O B O–Li OH O OH O H OEt H CHO OEt H H Me H Me Me H Me H Me
Representative aldol reactions of α-chiral aldehydes of the Cram type (= only H or alkyl groups at the α-center) with Z-enolates (assuming Cram-Felkin selectivity):
O–Li OH O H CHO OEt OEt Me H Me H H
CHEM 330 p.98
O B OH O CHO H Ph Me H Me H H
O–Li OH O N H CHO N H Me H Me H
Case of those aldehydes in which the one of the α-substituents is a heteroatom such as O, N, or halogen (F, Cl, etc.), for instance:
CHO MeO H
Principle: an α-heterosubstituted aldehyde, such as the one above, tends to react with nucleophiles in a manner that is opposite that anticipated on the basis of the Cram-Felkin reactivity model (phenyl = L; OMe = M; H = S):
OH "large" OH H Nu CHO Nu H Nu Nu MeO H MeO H MeO H "medium" "small" minor product expected on the basis major product expected on the basis of the Cram-Felkin reactivity model: of the Cram-Felkin reactivity model: in fact, major product of the rx. in fact, minor product of the rx.
The Felkin-Anh model of nucleophilic addition to an α-heterosubstituted aldehyde:
the aldehyde is most reactive when the C–X bond is approximately perpendicular to the plane of the C=O group. In this manner, mixing of the σ*C–X and the π*C=O orbitals creates a "hybrid" acceptor orbital of lower energy. This facilitates the nucleophilic addition process:
large lobe of the * mixing of π C=O X X π*C=O large lobe of new orbital with O O larger cross-section the * and σ*C–X H σ C–X (lower energy) orbitals H
There are two conformations of the aldehyde, A and B, in which the above condition is satisfied: CHEM 330 p.99
OMe OMe
A H O B O H H Ph H Ph
Nu Nu
However, conformation A is more reactive than B, because it is the one that allows the least degree of steric interaction between the incoming nucleophile and the substituents at the α position of the C=O
In general, an α–heterosubstituted aldehyde will be most reactive toward nucleophilic addition when it acquires the following conformation:
X where X = heteroatomic group (O, N, halogen,...) H O L = larger substituent (Ph in this case) S = smaller substituent (H in this case) S L
Nu
Note: the Felkin-Anh model coincides with the Cram-Felkin model if one assumes that the heteroatomic substituent behaves as the "large" group
Preferential reaction of the aldehyde in question with a nucleophile as indicated below:
OMe OH Re-face OMe H O H OH attack Nu H Ph MeO H steric H Ph interaction Nu Nu product formed selectively major product
Behavior of the aldehyde in question in aldol reactions (assuming Felkin-Anh selectivity), e.g.:
O–BCy2 OH O CHO (after aq. workup) MeO H MeO H Me
O–Li OH O H CHO OEt OEt H MeO H MeO H
Complications encountered in the course of a substrate-controlled, asymmetric aldol reaction of an α-chiral aldehyde: many effects not covered in CHEM 330 contribute to the stereochemical outcome of substrate-controlled reactions; for instance: CHEM 330 p.100
(a) the reaction of the Cram aldehyde and related substrates with E-enolates proceeds in accord with the Cram-Felkin reactivity model, but the reaction with Z-enolates may proceed with diminished – or even inverted – stereo- selectivity, due to a developing syn-pentane interaction within a Zimmerman- Traxler TS (cf. Roush, W. R. J. Org. Chem. 1991, 56, 4151):
O–Mt oxophilic metal, For the given configuration O Me so Zimmerman- of the α-carbon, the Cram- Z Traxler topology... Felkin model predicts H Si -face reactivity. So .... Me H generic Z-enolate
Z developing H bond Mt OH O O H H TROUBLE ! O Z H Ph H H Me syn-pentane Me expected Cram-Felkin product interaction !!
(b) the same may be true for the reactions of α-heterosubstituted aldehydes with enolates and other nucleophiles, with the added complication that the stereo- chemical outcome of the process depends on whether chelating metal ions are present in the reaction medium:
Mt but oxophilic, For the given MeO MeO O configuration O chelating Mt Ph ions will favor Ph of the α-carbon, H O the Felkin- a conformation H from which the Anh model MeO H H H H predicts Re -face aldehyde displays reactivity ... Re-face Si face reactivity: Nu Nu Si-face attack attack!!
Principle: the stereochemical outcome of an aldol process may be rationalized, and often predicted, on the basis of a detailed analysis of (presumed) transition states structures. This analysis must take into account factors beyond those we have addressed in class; in particular, steric interactions between the substituents attached to the α-carbon of the aldehyde and those connected to the enolate. A detailed analysis of (presumed) transition states structures involved in carbonyl addition, including aldol reactions, is well beyond the scope of CHEM 330. Accordingly, in this course we shall assume that α-chiral aldehydes always react according to the Cram-Felkin or the Felkin-Anh model, as appropriate, with the understanding that in reality this is not always the case.
CHEM 330 p.101
Limitations of substrate-controlled asymmetric reactions (chirality present in the substrate): the stereochemical preferences of the substrate permit the creation of only certain permutations of configurations in the products
Desirability of reagent-controlled processes (chirality present in the reagent)
Chiral auxiliaries: chiral segments that are temporarily connected to a molecule in order to exert stereocontrol in the course of a reaction
"Easy-on, easy-off" character of a good chiral auxiliary
Evans auxiliaries, e.g.:
O O
HN O HN O (Bn = benzyl) Bn
Description of the heterocyclic portion of an Evans auxiliary as an oxazolidinone
Preparation of Evans auxiliaries from natural L-aminoacids, e.g phenylalanine, valine...
Attachment of enolizable carbonyl segments to an Evans auxiliary, e.g.:
O O O O
HN O Cl N O (other methods are also applicable) Bn Et3N Bn
Imides: structures in which 2 carbonyl groups are connected to the same N atom
Substantial planarity of Evans imides due to resonance interactions and existence of two non-equivalent conformations on which such interactions are maximal:
Me O H O O O N H N O geometric O plane
Conformational properties of Evans complexes in the presence / absence of chelating oxophilic metals:
CHEM 330 p.102
electrostatic problem: carbonyl dipoles in the absence of point in opposite oxophilic metals ... O O carbonyl dipoles are O parallel directions N O O N O
Bn steric problem: bulky groups Bn bulky groups are are farther apart compressed together
unfavorable conformation favorable conformation
in the presence of Mt oxophilic metals ... O O favorable conformation due to metal chelation N O (Mt = oxophilic metal)
Bn
Note: all conformations are substantially planar to maximize resonance interactions
Principle: like amides, Evans imides form Z enolates selectively, e.g.:
O O OLi O LDA N O N O
Bn Bn
Conformational properties of Evans enolates: formation of a chelate:
Li OLi O Me O O O Li exists H O N O as .... N O N O Bn Bn geometric plane the Li is actually bound to both C=O oxygens: the molecule is essentially planar
Alkylation of Evans enolates: preferential attack from the face of the enolate opposite the bulky benzyl group (minimization of steric interactions), e.g.:
CHEM 330 p.103
Br Li Me O O O Br Li LDA O H O O N O N O N O Bn Bn the newly formed stereogenic C has the R configuration shorthand the electrophile for chiral approaches from O auxiliary Me the face opposite O the bulky Bn group H O Xc H N H O Bn
Relative electrophilic character of the 2 carbonyls of an Evans complex:
more electrophilic: O O less electrophilic: resonance interaction resonance interaction with N atom only -- R N O with N and O atoms -- reacts more rapidly reacts more slowly with nucleophiles with nucleophiles Bn
Facile removal of the Evans auxiliary from the product by saponification or transesterification:
R-configured product O O O O aq. LiOH N O O Li OH + Xc H H H then mild + Bn H3O (analogous to ester saponification)
as well as:
R-configured product O O O K2CO3 N O OMe + Xc H MeOH H Bn (reversible formation (analogous to transesterification) of small amt's of KOMe)
Note: saponification and transesterification reactions run under the above conditions are much faster than α-deprotonation. So, exposure of the products to LiOH or K2CO3 in MeOH for a short period of time induces rapid saponification / transesterification with no erosion of stereochemical integrity of the enolizable center. CHEM 330 p.104
Net result of alkylating an Evans enolate: control of the absolute configuration of the product (=asymmetric alkylation):
R-configuration S-configuration O O alkylation proceeds O with no control of the LDA, then absolute configuration OMe + OMe OMe H H of the newly formed Br stereocenter: (achiral) 50 : 50 racemic product (achiral)
R-configuration O O O LDA, then O O K2CO3 N O N O OMe Br H H (chiral) MeOH Bn (achiral) Bn
alkylation has now occurred with control of the absolute configuration of the newly formed stereocenter: enantioenriched product
Use of dibutylboron enolates in Evans aldol reactions:
Bu Bu B O O O Bu2B–OTf N O chelated B enolate O N O of Z geometry only Et3N Bn Bn
Note: the mechanism of formation of the Evans boron enolate is substantially the same as that seen earlier for ketones (notes of Nov 5 & Nov 8)
First interaction between an aldehyde (e.g. benzaldehyde) and an Evans boron enolate: release of the dative bond between the B and the oxazolidinone oxygen atoms and consequent internal rotation leading to a more stable conformation:
O Ph Bu Ph Bu O Ph O O Bu Bu H B H O B O H B O O Bu O N O Bu N O N O Bn Bn The bond-forming process may now occur Bn via a Zimmermann-Traxler-type TS . . .
Transition state model for the Evans aldol reaction:
CHEM 330 p.105
complex A above equatorial Ph Ph folds to allow the O O nucleophilic and Bu H H electrophilic centers B Bu B to interact. Folding Bu Bu occurs so as to H Me Me H minimize steric O interactions. Notice O pericyclic O O N N Aq. the equatorial H H orientation of the O mechanism O wrkp. phenyl group.
In red: incipient geometric bond plane Ph HO H
Me H OH O the reaction forms predominantly O O H the S, S-configured product. The H N Ph Xx syn diastereomer forms because a O H Z enolate is involved in the reaction Me
Principle: the above Evans auxiliary derived from (L)-phenylalanine forces the aldehyde to react from the Si face
Release of Xc from Evans aldol products by treatment with, e.g., MeOH/K2CO3 (after protection of the OH group):
O OH O TBSO O TBSO O H TBSCl H K2CO3 H + HN O Ph Xx Ph X Ph OMe H Et N H x MeOH H Me 3 Me Me Bn
Principle: the stereoselective preparation of the enantiomers of the alkylation or aldol products obtained as seen above would require the enantiomeric form of Evans auxiliary, i.e., one derived from an unnatural D-aminoacid. While some D-aminoacids are inexpensive, others, such as (D)-phenylalanine, (D)-valine, etc., are costly
Norephedrin and Evans auxiliary derived from it:
O H N OH COCl Evans auxiliary derived from norephedrin: a 2 2 HN O norephedrin: inexpensive naturally occurring H H H H alternative to auxiliaries derived aminoalcohol Me Ph base from unnatural D-aminoacids Me Ph
CHEM 330 p.106
Norephedrin-derived Evans auxiliary in the preparation of the enantiomer of the alkylation product seen earlier:
S-configuration S-configuration O O O O LDA, then K2CO3 O X OMe N H c H H H Br MeOH Me Ph
Norephedrin-derived Evans auxiliary in the preparation of the enantiomer of the aldol product seen earlier:
1. Bu BOTf O O 2 Et N HO O 3 H TBSCl N O Ph Xx H H 2. PhCHO H Et N Me 3 Me Ph 3. aq. wrkp.
TBSO O TBSO O K CO H 2 3 H Ph Xx Ph OMe H MeOH H Me Me
Principle: the above Evans auxiliary derived from norephedrin (or possibly one derived from a (D)-aminoacid) forces the aldehyde to react from the Re face
Application of the Evans aldol technology: macrolide antibiotics
O O O
OH OH ( Gly = sugars ) OH O HO O O–Gly O O–Gly O O–Gly O O–Gly O O Methymycin Erythromycin Narbomycin
The Prelog-Djerassi lactone ("PDL"): a product of chemical degradation of narbomycin and methymycin that may be used as a template for the synthesis of macrolide analogs
CHEM 330 p.107
oxidative O O cleavage O HO lactonize O Prelog- Djerassi O O COOH lactone
O O–Gly HO OH ester release sugar hydrolysis
Retrosynthetic logic for the Prelog-Djerassi lactone: stereochemical aspects
O release aldol lactone OH O O ROOC COOR ROOC COOH H esterify COOH's + syn relative config. O–Mt Z-enolate Xc
THUS, the aldol reaction must occur from the Re-face of the aldehyde. This requires the use of an Evans enolate based on the chiral auxiliary (Xc) derived from norephedrin:
Bu Bu B O O
N O
Ph
Important: conduct of the above aldol reaction under conditions of substrate control could be problematic, because:
(i) the desired product must form through addition of the enolate to the Re- face of the aldehyde (ii) the aldehyde has only C/H substituents at the α-stereogenic carbon, so its reactivity may be predicted using the Cram-Felkin model (iii) the Cram-Felkin model predicts preferential nucleophilic attack from the Si- face of the CHO group:
wrong L config. O O OH M Nu ROOC L O H L H H Nu S S S M Si-face M attack Nu
The Evans synthesis of the Prelog-Djerassi lactone (see Evans, D. A. Tetrahedron Lett. 1982, 23, 807, for complete details)
CHEM 330 p.108
O hydroboration/oxidation
O COOH aldol Prelog- OH O COOMe A: must be made Djerassi COOMe lactone enantioselectively
Stereochemical aspects of the above aldol reaction: interplay of innate stereochemical preferences of substrate and reagent
Principle: when a chiral substrate reacts with a chiral reagent ("double distereoselection"), the stereochemical preferences of one may reinforce ("match") or oppose ("mismatch") those of the other:
• matched substrate-reagent pairs tend to react with high stereoselectivity;
• mismatched substrate-reagent pairs tend to react with poor stereoselectivity
Mismatch in the above aldol reaction:
the Cram-Felkin model predicts Si-face reactivity for aldehyde A. However, the aldol reaction must proceed through Re-face addition. Hopefully, a norephedrin- derived Evans boron enolate such as the one shown below will be able to circumvent the innate stereochemical preferences of the aldehyde.
Bu Bu B O O
N O
Ph Enantioselective preparation of aldehyde A through alkylation of an Evans enolate:
O O I O
A Xc + Xc
Requirement for the Evans auxiliary derived from norephedrin for the implementation of this approach to A:
O O O redox chem. O 1. LDA needed to O X H N 2. c complete I the synthesis Ph ox. state A ox. state = +3 = +1
CHEM 330 p.109
The redox sequence: facile DIBAL reduction of the alkylation product to a primary alcohol but problematic oxidation of the latter to an aldehyde (e.g., with PCC or other oxidants) due to racemization
O OH O DIBAL [ O ] Xc H A
Successful Parekh-Doering oxidation of the alcohol to aldehyde A without erosion of stereochemical integrity:
O N S O O OH O H A DMSO, then Et3N
The Parekh-Doering oxidation: oxidation of primary alcohols to aldehydes and of secondary alcohols to ketones by reaction with DMSO and pyridine-SO3 complex, followed by Et3N
O N S O OH O O Note: oxidation of a secondary R R alcohol would give a ketone DMSO, then Et3N
DMSO as a potential oxidant: the S atom in DMSO is present at the oxidation state of 0, but the favorable oxidation state of S in organic compounds is –2 Kinetic stability of DMSO and consequent requirement for a suitable form of activation in order to express its oxidant properties
Presumed mechanism of the activation of DMSO with the pyridine-sulfur trioxide complex during the Parekh-Doering reaction:
N N O O H O O S N S O S O O S O S O S O O O R O R OH CHEM 330 p.110
SO 2– Me 4 Me O O S NEt3 O S R CH O S O S O R CH2 R O H H H H H unusually acidic C-H: upon addition of Et3N...
O + S R H
The Swern oxidation: a more recent, widely used oxidation method that involves the activation of DMSO with oxalyl chloride (Cl-CO-CO-Cl):
O Cl DMSO, OH Cl O O Note: oxidation of a secondary R R alcohol would give a ketone then Et3N H
Presumed mechanism of the Swern oxidation:
O Cl Cl O Cl S O Cl Cl S + CO2 + CO S O O Cl O chlorodimethylsulfonium chloride Then:
Cl H ±H+ Cl S Cl S O Cl S O HO R R R
Et3N S O (continue as seen for the Cl Parekh-Doering oxidation) R
The aldol step in the synthesis of the Prelog-Djerassi lactone: mismatched reactants
Bu Bu B O O O OH + N O COXc H Ph
CHEM 330 p.111
O OH O Nu H L L BUT .... Nu S S H M M the chirality of the The configuration of the OH-bearing carbon in α-center induces the major product of a nucleophilic C=O addition Si face reactivity would results from Si - face attack OH ... BUT: COXc
is the product of Re face attack. The Evans enolate causes the aldehyde to react "unnaturally" i.e. from the less reactive face. In other words, the aldehyde wants to react from the Si face, but the enolate forces it to react from the Re face mismatch
Extremely high level of diastereoselectivity in the reaction above (400 parts of desired product to 1 part of a mixture of 3 other stereoisomers!)
Ability of Evans enolates to circumvent innate stereochemical properties of aldehydes possessing an α-stereogenic carbon as one of the reasons for their success
Disiamyl borane (structure below): a hindered hydroboration agent that effects highly diastereoselective hydroboration reactions.
H B
Stereoselective hydroboration of the above aldol product after protection of the OH group as a TMS ether:
OH H SiMe3 1. disiamyl SiMe3 OH O O TMS-Cl O O borane O O N O Xc Xc Et3N 2. H2O2 aq. NaOH Ph 7 : 1 selectivity in favor of this diastereomer Synthesis of the Prelog-Djerassi lactone: the final oxidation
OH O SiMe3 O O [ ? ] O O
Xc Xc
CHEM 330 p.112
Greater nucleophilicity of primary alcohols (less sterically hindered) relative to secondary alcohols
Principle: the greater nucleophilicity of primary vs. secondary alcohols permits the selective oxidation of primary alcohols in the presence of secondary alcohols by the use of appropriate reagents – – Perrhuthenate ion, RuO4 : the Ru(VII) analog of permanganate ion (MnO4 )
Formation of perruthenate ion by the action of appropriate oxidants upon compounds containing Ru in lower oxidation states; e.g. (Ph3P)2RuCl2
N-methylmorpholine-N-oxide (NMO, structure below) as a common oxidant:
O
N O
The Sharpless perruthenate oxidation: reaction of primary and secondary alcohols with (Ph3P)2RuCl2 / NMO
Mechanism of perruthenate oxidation of primary and secondary alcohols to the corresponding carbonyl compounds:
H O O 1 OH O O R 1 Ru + OH R O ±H 1 O Ru 2 O R R O Ru O 2 O O H R 2 O O H R H primary or secondary O O R1 O OH N O Ru O R2 HO N aldehyde O or ketone
– Principle: RuO4 oxidizes primary alcohols to aldehydes faster than it oxidizes secondary alcohols to ketones.
Completion of the synthesis of the PDL
OH O O H H H SiMe3 1. pyridine • HF O O O O O O 2. (Ph P) RuCl 3 2 2 Xc OH Xc (cat.); NMO
CHEM 330 p.113
State-of-the-art in perruthenate oxidation of alcohols to carbonyls: use of catalytic tetrapropylammonium perruthenate ("TPAP") in the presence of NMO (Ley oxidation):
High cost and toxicity of OsO4
Ability of NMO to oxidize low valent forms of Os to OsO4
Use of NMO in catalytic osmylation reactions: the Upjohn osmylation
recycles
cat. H H (VIII) NMO Os O4 O O OH O O Os (VI) + Os (VIII) NMO O O OH O O H O H N organic product
Limitation of Evans technology: the method can only afford syn aldol products
The question of enantioselective creation of anti-aldol motifs
The Abiko-Masamune technology for anti-aldol assembly (1997):
O R1 R1 H N OH Cl Bn 2 O MesO2S N O O H H S O Me Ph N OH H H Me Ph norephedrine H H Me Ph Abiko-Masamune chiral auxiliary
1 R (E) O B Bn OH O OTf B(Cy)2 R2 H MesO2S N O O 2 R Xc H H Et N, –78° C Si-face R1 3 Me Ph selective
* * *
CHEM 330 p.114
G. Construction of 1,3-Diol Systems
The assembly of 1,3-di-OH systems of the type:
OH OH * * three stereocenters: eight R3 * R1 stereoisomers are possible R2 Preparation of 1,3-diol systems of the above type by reduction of an aldol product:
the OH group in OH O the aldol product OH OH the configuration of can direct C=O these stereogenic C's R3 R1 R3 R1 is fixed through an aldol R2 reduction to form R2 reaction either syn or anti this configuration diol stereoisomer is established by C=O reduction
Stereoselective reduction of a β-hydroxyketone to the anti-1,3-diol with sodium + – triacetoxyborohydride, Na BH(OAc)3 (Evans reduction), e.g.:
OH O OH OH NaBH(OAc)3 anti-1,3-diol Ph Et Ph Et Me Me
Stereoselective reduction of a β-hydroxyketone to the syn-1,3-diol with sodium + – borohydride, Na BH4 , in the presence of diethylboron methoxide, Et2BOMe (Prasad reduction), e.g.:
OH O NaBH4 OH OH syn-1,3-diol Ph Et Ph Et Me Et2BOMe Me
Presumed mechanism of the Evans reduction:
OAc AcO B H OAc acetoxy ligands are OH O O O H B OAc ± AcOH easily exchangeable + with alcohols: O Ph Et Ph Et Me Me O
H OAc H O H OH OH B OH H Ph Et Ph Et Ph Et Me AcO Me H O H OH Me
CHEM 330 p.115
Presumed mechanism of the Prasad reduction: Et Et B methoxy ligand is OH O O O ± MeOH easily exchangeable MeO–BEt + with alcohols: 2 Ph Et Ph Et Me Me H O H Et O Et Ph O B O BEt Me 2 Me Ph Et Et H H H Bottom-face attack causes the half-chair to advance to H3B–H a chair-like conformer
H OH OH OH OH Ph Et Ph Et Me H H Me
CHEM 330 p.116
H. Pericyclic Reactions: Diels-Alder Chemistry
Ionic reactions: processes that involve ionic intermediates (e.g., carbanions / enolates)
Radical reactions: processes that involve radical intermediates
Pericyclic reactions: a family of reactions that proceed only through the interaction of π systems, that may be described by a "circular" movement of electrons, and that involve neither ionic nor radical intermediates.
Cycloaddition reactions: processes that lead to formation of new rings through the interaction of independent π systems
Cycloaddition reactions encountered thus far: the addition of O3 and OsO4 to olefins
A typical cycloaddition process leading to C–C bond formation: the Diels-Alder reaction between an appropriately substituted 1,3-butadiene and an alkene:
heat R1 R2 R1 R2
R1, R2 : generic substituents connected to any C atom of the reactants
Description of the mechanism of the Diels-Alder reaction as a pericyclic movement of six electrons:
Dienophile: the "diene-loving" olefin that combines with the diene during a Diels-Alder reaction
Cycloadduct: the product of a cycloaddition reaction, e.g., of a Diels-Alder reaction
The Diels-Alder reaction as a concerted process; i.e., one that does not involve reactive intermediates (ions / radicals), and in which the product forms in a single kinetic step
E
+
rc
Principle: during a Diels-Alder reaction, electrons must flow from one component of the reaction to the other, through appropriate orbital interactions. Accordingly, all of the CHEM 330 p.117 following key aspects of the Diels-Alder reaction are defined by the details of how the molecular orbitals of one component interact with those of the other:
i. conformational: which conformation(s) of the diene promote the reaction
ii. stereochemical: relative configurations of newly formed stereocenters
iii. topological: relative faciality of diene / dienophile interaction
iv. regiochemical: relative orientation of diene and dienophile during the reaction
v. kinetic: how structure affects reactivity
Molecular π orbitals of diene and dienophile components of a Diels-Alder reaction:
diene dienophile
E 3 nodes E 1 node LUMO
2 nodes LUMO 0 nodes HOMO
1 node HOMO "fat dots" =nodes
0 nodes shaded / blank lobes =positive / negative phases of the atomic p orbitals
Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) of a molecule
The Diels-Alder reaction as one that involves the interaction of 4 π electrons associated with the diene and 2 π electrons associated with the dienophile; therefore, a 4π+2π cycloaddition
Principle: in a Diels-Alder reaction, and indeed in any reaction, electrons must flow from a populated πC=C molecular orbital of one component into a vacant π*C=C molecular orbital of the other component, and viceversa. Therefore, one can favor the process by creating a "voltage difference" between the components, i.e., by making one component electron-rich and the other electron-deficient
Substitution of Diels-Alder components with electron-donating (OMe, OSiR3, NMe2, alkyl, ...) or electron-withdrawing (C=O, CN, SO2R, NO2, ...) groups in order to make them electron-rich or electron-deficient
Regular demand Diels-Alder reactions: those in which the diene is electron rich and the dienophile is electron-deficient, e.g.:
CHEM 330 p.118
O O
butadiene: a O O fairly electron rich diene benzoquinone: Diels-Alder a very electron product deficient dienophile
Inverse demand Diels-Alder reactions: those in which the diene is electron-deficient and the dienophile is electron-rich, e.g:
O O O O
O O O O a very electron a very electron Diels-Alder adduct deficient diene rich dienophile
Historical primacy of regular-demand Diels-Alder reactions
Principle: the analysis of the interaction between the molecular orbitals of the diene and those of the dienophile during a Diels-Alder reaction is complex, but it may be simplified by considering just the interaction of the so-called "Frontier Molecular Orbitals" (FMO): the HOMO of the electron-rich reactant with the LUMO of the electron-deficient one (Fukui principle)
Principle: in any reaction, the electron-rich component may be thought as reacting primarily through its HOMO; the electron-deficient component, through its LUMO
Frontier molecular orbital (FMO) theory: a simplified treatment of chemical reactivity based on an analysis of HOMO(electron-rich component)-LUMO(electron-deficient component) interaction
Key molecular orbital interaction during a regular demand Diels-Alder reaction (=electron rich diene + electron-deficient dienophile): HOMO(diene) – LUMO(dienophile)
Molecular π orbitals of diene and dienophile components of a Diels-Alder reaction:
CHEM 330 p.119
diene dienophile
E 3 nodes E 1 node LUMO
2 nodes LUMO 0 nodes HOMO
1 node HOMO "fat dots" =nodes
0 nodes shaded / blank lobes =positive / negative phases of the atomic p orbitals
Symmetric (terminal p-type atomic orbitals have identical phases) and antisymmetric (terminal p-type atomic orbitals have opposite phases) molecular π orbitals
FMO analysis of regular-demand Diels-Alder reactions (electron-rich diene reacting with electron-deficient dienophile):
Because electrons must flow from the diene to the dienophile, the most significant orbital interaction will be the one between the HOMO of the diene (populated by electrons that can most readily be displaced toward an acceptor) and the LUMO of the dienophile (vacant orbital that can accommodate additional electrons). Notice that HOMO(diene) and LUMO(dienophile) are both antisymmetric orbitals.
Moreover, the HOMO(diene) – LUMO(dienophile) interaction causes the termini of the diene to become bonded to the termini of the dienophile. This requires that p orbitals associated \ with the terminal atoms of both components interact through lobes of like phase
1. Conformational aspects of the Diels-Alder Reaction:
s-cis and s-trans conformations of dienes:
H H unfavorable H H interaction H H H H s-trans conformer: H H s-cis conformer: less energetic more energetic H H
Requirement for an s-cis conformation of the diene in order to induce a Diels- Alder reaction:
ca. 1.35 Å ca. 1.35 Å LUMO of dienophile s-cis diene: s-trans diene: orbital interaction too far! orbital interaction , with dienophile with dienophile is not possible HOMO of is possible diene ca. 2.5 Å ca. 5 Å
Consequences of the requirement for an s-cis conformation of the diene in a Diels-Alder reaction: CHEM 330 p.120
undergoes does not isoprene: piperylene: Diels-Alder undergo more reactive less reactive more reactive less reactive reaction Diels-Alder in Diels-Alder in Diels-Alder in Diels-Alder in Diels-Alder reaction reactions reactions reactions reactions right side diene cannot access the 2-Me substituent in isoprene cis-Me group disfavors s-cis conformation diminishes the ΔE between s-cis conformation s-cis and s-trans conformers
2. Stereochemical aspects:
A Diels-Alder reaction leads to a cycloadduct that could be obtained in two diastereomeric forms. Consider the reaction of 1,3-butadiene with 1,4-benzoquinone:
O O O H H Important: we only care may form about relative configurations either or: (=diastereoselectivity): chiral H H molecules will form as racemates O O O which product does actually form?
lobes involved in the LUMO of bond-forming process the reaction is suprafacial dienophile are on the same face with respect to the dienophile (both below) of the plane of the π system
lobes involved in the HOMO of bond-forming process the reaction is suprafacial diene are on the same face with respect to the diene (both above) of the plane of the π system
The reaction is thus suprafacial with respect to both diene and dienophile, meaning that each component interacts with the other by utilizing lobes of the p- type orbitals composing the π system that are situated on the same face (top or bottom) of the respective molecular planes
CHEM 330 p.121
lobes involved in the bond-forming process O LUMO of H dienophile are on the same face (both below) of the plane of the π system H lobes involved in the O HOMO of bond-forming process diene are on the same face only product, because the (both above) of the reaction must be syn with respect to both components plane of the π system
We predict that the reaction must be strictly syn with respect to both components. This is readily verified by experiment. Indeed, no anti Diels-Alder reactions have ever been observed.
The Diels-Alder reaction (and related processes) as a 4πs + 2πs cycloaddition
note: interesting reactions of benzoquinone cycloadducts:
OH O O O cat. base H H H (e.g., Et3N, H2 cat.
NaOMe, Pd(C) base DBU, ...) H H H OH O O O a cis-decalone: trans-decalone: less stable more stable
3. Topological aspects of the Diels-Alder reaction:
Principle: a 4πs + 2πs cycloaddition can occur with two different topologies, leading to two diastereomeric forms of the cycloadduct. Example: the reaction of benzoquinone with (E,E)-2,4-hexadiene:
O H O H O H H H H O 4π +2π Me s s O Me H H H H H O Me H Me isomer A exo - topology
In the exo mode of reactivity, the bulk of the dienophile occupies a region of space that is opposite that containing the bulk of the diene. The term exo derives from the fact that most of the dienophile molecule occupies a region of space external to that occupied by the diene
CHEM 330 p.122
O H O O H H H H O 4πs+2πs H Me O Me
H H H H H H O Me Me isomer B endo - topology
In the endo mode of reactivity, the bulk of the diene and of the dienophile occupy the same region of space. The term endo derives from the fact that most of the dienophile molecule occupies a region of space internal to that occupied by the diene
will the reaction occur diastereoselectively, and – if so – which isomer, A or B, will form preferentially?
Principle: the exo topology is favored on steric grounds (less steric compression), but the endo topology is favored on electronic grounds, due to secondary orbital interactions:
O O O LUMO of H H H H dienophile H 4π +2π - endo O H s s O Me Me H H H HOMO of H H O diene H Me isomer B Me major product black dashed lines: primary orbital interactions. These are responsible for bond formation. red dashed lines: secondary orbital interactions. These assist bond formation
O O H H O LUMO of H H dienophile H H 4πs+2πs - exo O O Me HOMO of Me H H H O diene H H H Me isomer A Me minor product no possibility of secondary orbital interactions
Principle: secondary orbital interactions are believed to promote the cycloaddition process by "compacting" the diene-dienophile complex, thereby facilitating the Diels- Alder reaction, and by providing additional electron delocalization, thereby lowering the electronic energy of the diene-dienophile complex.
note: explanations other that those involving secondary orbital interactions have been advanced for the endo preference in Diels-Alder reactions. The relative merits of the various explanations are a matter of scientific controversy.
CHEM 330 p.123
The Alder endo rule: the endo topology is normally favored in Diels-Alder reactions
Description of the Diels-Alder reaction as a 4πs + 2πs endo cycloaddition
Stereochemical consequences of the endo preference of the Diels-Alder reaction:
O O H O H H O maleic anhydride: H a reactive dienophile Me OMe O H H H endo TS: overall H exo TS: overall Me favored Me disfavored O H O H O H H O O H H O H H O Me O O Me O H H H H O H H H O Me H Me minor product major product black: primary orbital interaction red: secondary orbital interaction
O cyclopentadiene: very benzoquinone: very reactive Diels-Alder electron-deficient and diene - undergoes highly reactive Diels- D-A reaction with itself Alder dienophile at room temperature ! O exo-cycloaddition endo-cycloaddition (not observed) (actual outcome)
O H H O O O H O O H O endo cycloaddduct exo cycloadduct O not formed observed product
black: primary orbital interaction red: secondary orbital interaction
Reversibility of the Diels-Alder reaction at sufficiently high temperatures: case of cyclopentadiene monomer-dimer equilibrium:
very reactive T < 160°C H diene: undergoes H 4πs + 2πs Diels-Alder reaction endo product with itself at room temp. T > 160°C
CHEM 330 p.124
Reversibility of certain Diels-Alder reactions even at / near room temperature: the case of furan reacting with maleic anhydride:
O furan • weakly aromatic character of furan • rapid equilibration of furan and maleic anhydride with the less thermodynamically favorable endo adduct at room temperature • facile reversibility of the process
Principle: a hypothetically reversible Diels-Alder reaction might produce the more thermodynamically favorable exo-cycloadduct: the case of furan + maleic anhydride
O O O O + O O H O O H exo adduct the reversibility of the D-A reaction of furan causes a switch from kinetic to thermodynamic control, leading to the accumulation of the more thermodynamically favorable exo adduct:
Principle: in general, Diels-Alder endo cycloadducts are less thermodynamically favorable (= more energetic) than exo cycloadducts
The preference for the endo topology in the Diels-Alder reaction as a kinetic effect
Facile occurrence of reverse Diels-Alder reactions proceeding with the expulsion of a small, highly thermodynamically stable molecule such as SO2, CO2, N2; e.g.:
COOEt O O COOEt O 100°C COOEt + CO2 O COOEt COOEt COOEt diethyl phthalate: α-pyrone: a fairly diethyl acetylene observed product reactive D-A diene dicarboxylate: a unstable cycloadduct: it reactive dienophile readily undergoes retro- D-A loss of CO2 to form an aromatic ring
Interest of the above reactions in the synthesis of complex aromatic compounds
Intramolecular Diels-Alder reactions: those in which diene and dienophile are tethered to become part of the same molecule
General preference for endo-topology in intramolecular Diels-Alder reactions, provided that the dienophile can establish secondary orbital interactions with the diene: CHEM 330 p.125
Ph notice the pseudoequatorial orientation of the benzyl group H Ph H H heat H Ph H MeO H MeOOC MeOOC O H major cycloadduct endo-topology
black: primary orbital interaction red: secondary orbital interaction
Creation of orthoquinodimethanes through retro-Diels-Alder expulsion of SO2 from appropriate aromatic sultones
O heat, X=Y X S Y O – SO2 a sultone orthoquinodimethane: undergoes rapid D-A reaction even with simple olefins (formation of an aromatic benzene ring)
Ortho-quinodimethanes as extremely reactive dienes in Diels-Alder reactions
Example of a Diels-Alder reaction that proceeds in the exo-mode because of the lack of opportunity for secondary orbital interactions:
O O exo-topology heat favored on O H H steric grounds S – SO2 MeO MeO O there are no activating substituents on the dienophile: no possibility of secondary orbital interactions notice chair O conformation H H O Diels- H H Alder MeO H exo cycloaddition product: H estrone methyl ether
CHEM 330 p.126
Principle: a Diels-Alder reaction will proceed in the exo-mode (less sterically demanding) in cases where no secondary orbital interactions can subsist.
4. Regiochemical aspects:
Principle: an unsymmetrical diene could react with an unsymmetrical dienophile through two distinct 4πs+2πs endo transition states. These differ for the relative orientation of the reactants and lead to the formation of two regioisomeric products
Example: the reaction of 1-methoxybutadiene with acrylonitrile:
H H OMe OMe MeO H CN CN 4πs+2πs H MeO + H H endo N NC H H endo-topology black: primary orbital interaction red: secondary orbital interaction
OR
OMe OMe H OMe H H CN 4πs+2πs + H H endo H NC CN N H OMe H endo-topology black: primary orbital interaction red: secondary orbital interaction
Regiochemical course of most (but not all) Diels-Alder reactions as a function of atomic polarity: the nucleophilic atom of the electron-rich component (the diene, in a regular demand Diels-Alder reaction) tends to connect to the electrophilic atom of the electron- deficient component (the dienophile, in a regular demand Diels-Alder reaction):
OMe OMe N N
site of greatest site of greatest electron density electron deficiency
CHEM 330 p.127
OMe OMe CN 4πs+2πs CN so, the preferred orientation is: endo major product (racemic)
alternatively:
OMe OMe N 4πs+2πs CN (–) (+) (–) major product (racemic) (+) (+) endo (–)
matched polarity favored
OMe OMe 4πs+2πs (–) (+) (+) minor product (racemic) (+) (–) endo (–) CN N mismatched polarity disfavored
Regiochemical course of most (but not all) Diels-Alder reactions as a function of atomic polarity - additional examples:
"–" terminus "+" terminus Alkyl R Alkyl R 4πs + 2πs + Z endo Z R = Me, OAc, Z = CN, COOMe, OMe, OSiMe3 CHO, COMe, NO2
R O R O Me H Me 4πs + 2πs + O O "–" terminus "+" endo terminus O H O R = Me, OAc, citraconic OMe, OSiMe3 anhydride
CHEM 330 p.128
"–" terminus TMSO "+" terminus TMSO 4πs + 2πs + COOMe endo COOMe OMe OMe Danishefsky diene: reactive diene (very electron- rich) that undergoes highly regioselective D-A reactions (electron-donating groups work in synergy)
EtOOC EtOOC OMe TBSO OMe TBSOTf TBSO
i-Pr NEt O NC O 2 NC TBS
COOEt OMe TBSO OTBS CN
Principle: regiochemical predictions based on atomic polarity are rooted in a coarse approximation of what actually happens when molecular orbitals interact. Although the vast majority of Diels-Alder reactions of interest in the synthesis of biologically active substances follow the above trends, exceptions are known (example below). Details of such exceptional cases are beyond the scope of CHEM 330.
CHO nonetheless: 2 O O O O O CHO
5. Kinetic aspects:
Steric effects and magnitude of the HOMO-LUMO gap and as the key factors that affect the rate of a Diels-Alder reaction
In a Diels-Alder reaction, electrons from the HOMO of the electron-rich component must flow into the LUMO of the electron-deficient component. To do so, electrons from the HOMO of one component must "jump the gap" that separates them from the LUMO of the other component. For instance, in the regular demand Diels-Alder reaction between butadiene (e– rich diene) and acrolein (e– deficient dienophile):
CHEM 330 p.129
E LUMO CHO
ΔEHOMO(diene)–LUMO(dienophile)
HOMO
Principle: the rate of a Diels-Alder reaction increases with decreasing ΔE HOMO– LUMO
reminder: the energy of an orbital is defined as the energy that is released when an electron coming from an infinitely distant point falls into, and occupies, that orbital
Narrowing the ΔEHOMO(diene)–LUMO(dienophile) during a Diels-Alder reaction by:
- raising the HOMO energy, or
- lowering the LUMO energy, or
- simultaneously raising the HOMO and lowering the LUMO energies
Modulating the ΔEHOMO(diene)–LUMO(dienophile) during a regular demand Diels-Alder reaction:
Increasing the energy of the HOMO(diene) through the introduction of electron-donating groups (Me, OMe, NMe2, OSiMe3, etc.):
reactivity of isoprene and E (eV, MNDO) 2-methoxybutadiene LUMO CN toward - e.g. - acrylonitrile – 0.1
ΔE1 ΔE Me MeO HOMO 2 – 8.9 2-methoxybutadiene MB HOMO reacts faster – 9.2 IP isoprene 2-methoxybutadiene
Decreasing the energy of the LUMO(dienophile) through coordination with an appropriately selected Lewis acid: the reaction of 1-methylbutadiene (piperylene) with acrolein:
E (eV, MNDO)
LUMO CHO reactivity of – 0.1 piperylene The reaction is LUMO O toward free BF accelerated by – 2.0 3 acrolein and Lewis acid activation ΔE acrolein 1 of the dienophile ΔE2 activated by BF3 – 9.1 HOMO
Greater endo-selectivity of Diels-Alder reactions promoted by Lewis acid activation of the dienophile:
CHEM 330 p.130
a. the reaction of piperylene with acrolein:
endo TS – free acrolein
H LUMO of larger HOMO-LUMO gap: H H dienophile HOMO-LUMO H CHO interaction less facile H H O weaker secondary orbital interactions – diminished endo selectivity (no formal charge major – slower rate product HOMO H on C=O) Me of diene
endo TS – activated acrolein H LUMO of smaller HOMO-LUMO gap: H H dienophile HOMO-LUMO H CHO interaction more facile F3B O H H stronger secondary – enhanced endo selectivity orbital interactions – faster rate (formal + charge major HOMO on C=O) product of diene H Me
Principle: intramolecular Diels-Alder reactions that would form a strained product through an endo-topology tend to proceed slowly and to yield significant amounts of the exo product. In such cases, Lewis acid catalysis accelerates the reaction and increases endo-selectivity to a substantial extent. Example:
CHEM 330 p.131
MeOOC H H endo product H trans-fused 5-6 MeO system:strained H O MeOOC H endo: strained H MeOOC H exo product H cis-fused 5-6 MeO system: ~ no strain H O H exo: ≈ strain-free
Beneficial effect of Lewis acid catalysis on reaction rate and endo-selectivity:
• no Lewis acid catalyst: heat, slow nearly 1 : 1 mixture of endo and exo products formed (reaction is nonselective)
• with Et2AlCl: room temp., fast endo-product only
Diels-Alder reactions (and pericyclic reactions in general) as powerful transformations for the construction of carbon architectures of the type found in molecules of biomedical interest, especially when combined with the reactions discussed earlier in the course
Massive volume of literature describing applications of the Diels Alder reaction to the synthesis of biologically relevant molecules