The Stereogenic Center

FIGURE 7.1 A molecule with four different groups attached to a single carbon is chiral. Its two mirror-image forms are not superposable. 

An article in the December 1987 issue of the Journal of Chemical Education gives a thorough discussion of molecular chirality and some of its past and present terminology. 

FIGURE 7.2 Mirror-image forms of chiorodifiuo-romethane are superposabie on each other. Chiorodifiuo-romethane is achirai. 

Noting the presence of one (but not more than one) stereogenic center in a molecule is a simple, rapid way to determine that it is chiral. For example, C-2 is a stereogenic center in 2-butanol it bears a hydrogen atom and methyl, ethyl, and hydroxyl groups as its four different substituents. By way of contrast, none of the carbon atoms bear four different groups in the achiral alcohol 2-propanol. 

SAMPLE SOLUTION A stereogenic carbon has four different substituents, (a) In 2-bromopentane, C-2 satisfies this requirement, (b) None of the carbons in 3-bromopentane have four different substituents, and so none of its atoms are stereogenic centers. 

FIGURE 7.2 M irror-image forms of chlorodifluo-romethane are superposable on each other. Chlorodifluo-romethane is achirai. 

Molecules with stereogenic centers are very common, both as naturally occurring substances and as the products of chemical synthesis. (Carbons that are part of a double bond or a triple bond can t be stereogenic centers.) 

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The related 2-/-butyl derivative has also been prepared and used to advantage as a temporary protective group for the stereogenic center of amino acids during alkylations. ... 

The 2-alkyl derivatives have been prepared to protect the stereogenic center of the a-hydroxy acid during alkylations. ... 

Further evidence for a bromine-bridged radical comes from radical substitution of optically active 2-bromobutane. Most of the 2,3-dibromobutane which is formed is racemic, indicating that the stereogenic center is involved in the reaction. A bridged intermediate that can react at either carbon can explain the racemization. When the 3-deuterated reagent is used, it can be shown that the hydrogen (or deuterium) that is abstracted is replaced by bromine with retention of stereochemistry These results are also consistent with a bridged bromine radical. 

This unexpected outcome clearly implicated an important stereodirecting role for the dioxolane oxygens. To clarify the significance of having oxygen atoms bound to the stereogenic centers. Mash carried out an important control experiment by exam-... 

The stereochemical outcome of the reaction is determined by the geometry of the transition state for the Claisen rearrangement a chairlike conformation is preferred,and it proceeds strictly by an intramolecular pathway. It is therefore possible to predict the stereochemical course of the reaction, and thus the configuration of the stereogenic centers to be generated. This potential can be used for the planning of stereoselective syntheses e.g the synthesis of natural products. 

Mechanistically the observed stereospecificity can be rationalized by a concerted, pericyclic reaction. In a one-step cycloaddition reaction the dienophile 8 adds 1,4 to the diene 7 via a six-membered cyclic, aromatic transition state 9, where three r-bonds are broken and one jr- and two cr-bonds are formed. The arrangement of the substituents relative to each other at the stereogenic centers of the reactants is retained in the product 10, as a result of the stereospecific y -addition. 

The Diels-Alder reaction of a diene with a substituted olefinic dienophile, e.g. 2, 4, 8, or 12, can go through two geometrically different transition states. With a diene that bears a substituent as a stereochemical marker (any substituent other than hydrogen deuterium will suffice ) at C-1 (e.g. 11a) or substituents at C-1 and C-4 (e.g. 5, 6, 7), the two different transition states lead to diastereomeric products, which differ in the relative configuration at the stereogenic centers connected by the newly formed cr-bonds. The respective transition state as well as the resulting product is termed with the prefix endo or exo. For example, when cyclopentadiene 5 is treated with acrylic acid 15, the cw fo-product 16 and the exo-product 17 can be formed. Formation of the cw fo-product 16 is kinetically favored by secondary orbital interactions (endo rule or Alder rule) Under kinetically controlled conditions it is the major product, and the thermodynamically more stable cxo-product 17 is formed in minor amounts only. 

The final step is the nucleophilic displacement of the oxyphosphonium group by the carboxylate anion via a SN2-mechanism, yielding ester 3 with inverted configuration at the stereogenic center, and triphenylphosphine oxide. A hydrolysis of the ester 3 will leave the new configuration unchanged, and yield the inverted alcohol 4 ... 

Johnson s classic synthesis of progesterone (1) commences with the reaction of 2-methacrolein (22) with the Grignard reagent derived from l-bromo-3-pentyne to give ally lie alcohol 20 (see Scheme 3a). It is inconsequential that 20 is produced in racemic form because treatment of 20 with triethyl orthoacetate and a catalytic amount of propionic acid at 138 °C furnishes 18 in an overall yield of 55 % through a process that sacrifices the stereogenic center created in the carbonyl addition reaction. In the presence of propionic acid, allylic alcohol 20 and triethyl orthoacetate combine to give... 

Unsaturated -lactone 34 adopts a well-defined conformation and provides a suitable platform for the introduction of the stereogenic center at C-24 (monensin numbering). Catalytic hydrogenation of the carbon-carbon double bond in 34 takes place preferentially from the less hindered side of the molecule and provides an 8 1 mixture of stereoisomers in favor of 35 (100% yield). Cleavage of -lactone 35 with concentrated hydriodic acid at 130°C, followed by treatment of the resultant iodide 36 with triphenylphosphine, completes the synthesis of intermediate 19. 

When a cold (-78 °C) solution of the lithium enolate derived from amide 6 is treated successively with a,/ -unsaturated ester 7 and homogeranyl iodide 8, intermediate 9 is produced in 87% yield (see Scheme 2). All of the carbon atoms that will constitute the complex pentacyclic framework of 1 are introduced in this one-pot operation. After some careful experimentation, a three-step reaction sequence was found to be necessary to accomplish the conversion of both the amide and methyl ester functions to aldehyde groups. Thus, a complete reduction of the methyl ester with diisobutylalu-minum hydride (Dibal-H) furnishes hydroxy amide 10 which is then hydrolyzed with potassium hydroxide in aqueous ethanol. After acidification of the saponification mixture, a 1 1 mixture of diastereomeric 5-lactones 11 is obtained in quantitative yield. Under the harsh conditions required to achieve the hydrolysis of the amide in 10, the stereogenic center bearing the benzyloxypropyl side chain epimerized. Nevertheless, this seemingly unfortunate circumstance is ultimately of no consequence because this carbon will eventually become part of the planar azadiene. 

The stereoselectivity of an addition reaction is considerably lower when the reactions are conducted in polar solvents, complexing additives such as /V./V,A. A, -tetramethylethylenedi-arnine arc used, or when the stereogenic center carries a methoxy group instead of a hydroxy group. This behavior is explained as competition between the cyclic model and a dipolar model, proposed for carbonyl compounds bearing a polar substituent such as chlorine with a highly... 

In contrast to the open-chain and dipolar models, which are based on conformations of the carbonyl compound not representing energy minima, Karabatsos proposed a different model assuming an early, reactant-like transition state in which the most stable conformation of the free carbonyl compound is preserved1314. Thus, the C-M bond eclipses the carbonyl double bond and, in order to minimize the energy of the transition state, the nucleophile approaches close to the small substituent on the stereogenic center (Figure 5). 

Nonperpendicular attack of the nucleophile explains Felkin s hypothesis for the predominance of interactions involving R1 and R2 over interactions involving the carbonyl oxygen. Additionally, as R1 increases in bulk, the nucleophile is pushed towards the stereogenic center and can better feel" the difference between the substituents, resulting in an increase in stereoselectivity. 

In accord with the Felkin-Anh model, a-chiral ketones react more diastereoselectively than the corresponding aldehydes. Increasing steric demand of the acyl substituent increases the Cram selectivity. Due to the size of the acyl substituent, the incoming nucleophile is pushed towards the stereogenic center and therefore the diastereoface selection becomes more effective (see also Section 1.3.1.1.). Thus, addition of methyllithium to 4-methyl-4-phenyl-3-hexanonc (15) proceeds with higher diastercoselectivity than the addition of ethyllithium to 3-methyl-3-phenyl-2-pen-tanone (14)32. 

With a-alkyl-substituted chiral carbonyl compounds bearing an alkoxy group in the -position, the diastereoselectivity of nucleophilic addition reactions is influenced not only by steric factors, which can be described by the models of Cram and Felkin (see Section 1.3.1.1.), but also by a possible coordination of the nucleophile counterion with the /J-oxygen atom. Thus, coordination of the metal cation with the carbonyl oxygen and the /J-alkoxy substituent leads to a chelated transition state 1 which implies attack of the nucleophile from the least hindered side, opposite to the pseudoequatorial substituent R1. Therefore, the anb-diastereomer 2 should be formed in excess. With respect to the stereogenic center in the a-position, the predominant formation of the anft-diastereomer means that anti-Cram selectivity has occurred. 

The addition of dibutylcupratc to the a-substituted /1-formyl esters 1 preferentially affords, via chelation control, the cw-disubstituted y-lactone 241. These results are in agreement with those found with a-unsubstituted /1-esters39-41 (vide supra), assuming a seven-membered chelate as transition state of the addition reaction. The diastercosclectivity is somewhat lower with esters 1 as the stereogenic center is one carbon atom further removed from the reaction center and therefore the steric influence of the substituent R1 is less pronounced. 

The lower diastereoselectivity found with aldehyde 15 (R = CH3) can be explained by the steric influence of the two methyl substituents in close vicinity to the stereogenic center, which probably diminishes the ability of the ether oxygen to coordinate. In contrast, a significant difference in the diastereoselectivity was found in the additions of phenyllithium and phenylmagnesium bromide to isopropylidene glyceraldehyde (17)58 (see also Section 1.3.1.3.6.). Presumably the diastereo-sclcctivity of the phenyllithium addition is determined by the ratio of chelation-controlled to nonchelation-controlled attack of the nucleophile, whereas in the case of phenylmagnesium bromide additional chelation with the / -ether oxygen may occur. Formation of the -chelate 19 stabilizes the Felkin-Anh transition state and therefore increases the proportion of the anZz -diastereomeric addition product. 

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