REACTIONS THAT PRODUCE STEREOGENIC CENTERS

We have studied several reactions that yield products with stereogenic centers from compounds with no stereogenic centers. What prediction can we make about the configuration of the product The reaction of an achiral radical described previously shows that chiral products cannot form firom the reaction of achiral reactants. Molecules with stereogenic centers can form, however, the enantiomers form in equal amounts. 

---

Assuming that Grignard reagent addition to a carbonyl is a diastereoselective reaction that produces racemic products, it is important to ask if it is possible for the reaction to be enantioselective. If we rely on the carbon bearing the magnesium atom, the answer is no. If we incorporate a stereogenic center elsewhere in the molecule, however, the answer may be yes. For purposes of this discussion, the relative merits of the four cases listed above will be discussed. 

The Diels-Alder reaction generates new stereogenic centers from an alkene and a diene, which have no stereogenic centers (see Chapter 9, Section 9.1). The reaction will produce different diastereomers as well as different enantiomers. In addition, the orientation of substituents on the alkene or diene may lead to different positional isomers (regioisomers). It is therefore appropriate to discuss briefly the factors that influence the stereochemistry of the Diels-Alder product. 

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... 

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. 

A disadvantage of the THP group is the fact that a new stereogenic center is produced at C(2) of the tetrahydropyran ring. This presents no difficulties if the alcohol is achiral, since a racemic mixture results. However, if the alcohol is chiral, the reaction gives a mixture of diastereomers, which may complicate purification and/or characterization. One way of avoiding this problem is to use methyl 2-propenyl ether in place of dihydropyran (abbreviated MOP, for methoxypropyl). No new chiral center... 

The reaction can be carried out intramolecularly to produce, in one step, three new rings in moderate yield (Equation (36)).149 It is noteworthy that up to six stereogenic centers could be formed. Additionally, cobalt-catalyzed [4 + 2 + 2]-cycloadditions of bicyclo[2.2.2]octadienes have been reported (Equations (37) and (38)).150... 

The essence of asymmetric synthesis is producing a new stereogenic center in such a manner that the product consists of stereoisomers in unequal amount. In most cases, this can be achieved by the formation of a new sp3 stereocenter. There is also another type of asymmetric reaction in which the employed substrates contain either a stereogenic unit or a pro-stereogenic unit apart from the functional group, and asymmetric synthesis occurs even though the nature of the reaction is not directly related to the newly formed sp3 stereocenter. The Wittig reaction is invoked for the asymmetric synthesis of such molecules.47... 

DHAP-dependent aldolases produce 2-keto-3,4-dihydroxy adducts with high control of the configuration of the two newly formed stereogenic centers. However, while it can be assumed that the absolute configuration at C3 is independent on the acceptor used in the reaction, the configuration of the stereocenter generated from the addition to the aldehyde (C4 position) in some cases may depend on the structure and stereochemistry of the acceptor [6]. 

Dynamic Resolution of Chirally Labile Racemic Compounds. In ordinary kinetic resolution processes, however, the maximum yield of one enantiomer is 50%, and the ee value is affected by the extent of conversion. On the other hand, racemic compounds with a chirally labile stereogenic center may, under certain conditions, be converted to one major stereoisomer, for which the chemical yield may be 100% and the ee independent of conversion. As shown in Scheme 62, asymmetric hydrogenation of 2-substituted 3-oxo carboxylic esters provides the opportunity to produce one stereoisomer among four possible isomers in a diastereoselective and enantioselective manner. To accomplish this ideal second-order stereoselective synthesis, three conditions must be satisfied (1) racemization of the ketonic substrates must be sufficiently fast with respect to hydrogenation, (2) stereochemical control by chiral metal catalysts must be efficient, and (3) the C(2) stereogenic center must clearly differentiate between the syn and anti transition states. Systematic study has revealed that the efficiency of the dynamic kinetic resolution in the BINAP-Ru(H)-catalyzed hydrogenation is markedly influenced by the structures of the substrates and the reaction conditions, including choice of solvents. 

Although the E2 reaction does not produce products with tetrahedral stereogenic centers, its transition state consists of four atoms that react at the same time, and they react only if they possess a particular stereochemical arrangement. 

The development of efficient methods to access complex molecules vdth multiple stereogenic centers continues to be a formidable challenge in both academe and industry. One approach is the use of catalytic enantioselective cascade reactions [68] that have emerged as powerful tools to rapidly increase molecular complexity from simple and readily available starting materials, thus producing enantioenriched compounds in a single operation. 

---