Amide Auxiliaries

Radicals substituted a to the amide linkage, 24, have been used in several studies to control stereochemistry in radical transformations, while radicals substituted a to esters, 25, and ethers, 26, have been used on a few occasions. Resonance structures for each of these radicals (A and B) can be written as shown in 24-26, with stabilization resulting from delocalization of the odd electron into the adjacent functional group. This resonance delocalization also restricts the geometry of these radicals, maximum delocalization being obtained when overlap between the radical and adjacent group is highest. 

Several strategies have been used to control the conformation about the carbonyl-nitrogen bond of carboxamide radicals, and several of these approaches shown in carboxamides or carboximides have all proved to be useful auxiliaries for controlling the configuration of new stereogenic centers formed from prostereogenic radicals. 

Dimethylpyrrolidine and its analogs are efficient stereocontrol elements, since the C2 axis of the pyrrolidine makes the conformation about the carbonyl-nitrogen bond irrelevant. In radicals such as 27, both conformations provide essentially the same stereochemical environment for the radical center. An example of the use of dimethylpyrrolidine, is shown in Fig. 4. In this transformation, a /cr/-butyl ETOC ester is reacted with the acryloyl carboxamide of dimethylpyrrolidine and the addition product is isolated in excellent yield and selectivity. The propagation sequence involves addition of a tert-h xty radical to the acrylamide, trapping of the adduct radical, 27, by the PTOC ester, and decarboxylation of the pivaloyl carboxy radical. This transformation may be initiated thermally or photochemically, and photoinitiation at reduced temperatures gives product with higher diastereoselectivity. A 

6 1 mixture of diastereomers is obtained at room temperature and the product that is favored is the one shown in Fig. 4 [26], 

Radicals such as 27 add to alkenes and abstract halogen from bromotrichloro-methane selectively [27], In each case, selectivities in excess of 10 1 are obtained and the observed product is as predicted based upon the proposed structure of the radical. The proximal methyl of the dimethylpyrrolidine protects one face of the radical from reaction. 

---

A series of other ot,(3-unsaturated amide auxiliaries have been used for 1,3-dipolar cycloadditions, in particular for reactions of nitrile oxides (Scheme 12.54). 

This type of reaction can also be performed with acrylates bearing chiral alcohol or amide auxiliaries (see Section 2.2.2.3.2.1.1.1.). For example, with l,l-dimethyl-2-methylenecyclo-propane (6) and the chiral acrylate 11, the [3 + 2] cycloadduct 12 can be obtained in 86 /o yield almost diastereospecifically. With chiral acrylic esters, diastereoselectivities are usually in the range of 30-85% de. ... 

A "heterocyclic" strategy used an oxazolidone ring as a protected carboxyl (an amide) which also served as a chiral auxiliary. Treatment of 6.127 with a boron triflate, for example, gave boron enolate reagent 6.128 in situ, and it reacted with N-Boc leucinal to form 6.129. Boron enolates have been used in many syntheses as an alternative to lithium or sodium enolate in Aldol reactions.S7 Hydrogcnolysis of the methylthio moiety gave a methylene moiety and treatment of the amide auxiliary with base gave 6.95 (24% overall yield). 

Scheme 4.6 Alkylation of glycine through the amide auxiliary 30.

There have been recent remarkable advances in the field spearheaded by Ellman, who has described the use of optically active N-tert-butylsulfinyl imines 82. As a consequence of Ellman s intense activity in this area, this has evolved into a highly convenient and exceedingly versatile auxiliary for the asymmetric synthesis of a wide range of amines [27]. A key feature in the development of the tert-butyl sulfinyl amide auxiliary is its straightforward... 

In a more recent study on 1,3-dipolar cycloaddition reactions the use of succi-nimide instead of the oxazolidinone auxiliary was introduced (Scheme 6.19) [58]. The succinimide derivatives 24a,b are more reactive towards the 1,3-dipolar cycloaddition reaction with nitrone la and the reaction proceeds in the absence of a catalyst. In the presence of TiCl2-TADDOLate catalyst 23a (5 mol%) the reaction of la with 24a proceeds at -20 to -10 °C, and after conversion of the unstable succinimide adduct into the amide derivative, the corresponding product 25 was obtained in an endojexo ratio of <5 >95. Additionally, the enantioselectivity of the reaction of 72% ee is also an improvement compared to the analogous reaction of the oxazolidinone derivative 19. Similar improvements were obtained in reactions of other related nitrones with 24a and b. 

Table 6. Amides 13 by Removal of the Chiral Auxiliary from Iron-Acyl Complexes 12 n1 R4 R1...

Chiral Auxiliaries at Ester and Amide Groups a,/MJnsaturated Esters... 

As shown in scheme 1, (S)-amide 2 (ref. 4) obtained from ethyl ester of (S)-proline, chiral auxiliary and 2-substituted-2-propenoic acids 1 are bromolactonized with N-bromosuccinimide (NBS)-DMF, followed by hydrolysis with 6N-HC1 to afford (S)-4. The results are summarized in Table 1. 

Using a chiral auxiliary via the amide" or ester" leads to asymmetric induction. 

The reactions proceed via a phase-transfer mechanism [23]. The amine diffuses from the aqueous phase into the organic phase and reacts with the acid chloride. The amide formed remains in the organic phase, while the salt generated from the released HCI and the auxiliary base is transferred to the aqueous phase. 

A number of other types of chiral auxiliaries have been employed in enolate alkylation. Excellent results are obtained using amides of pseudoephedrine. Alkylation occurs anti to the a-oxybenzyl group.93 The reactions involve the Z-enolate and there is likely bridging between the two lithium cations, perhaps by di-(isopropyl)amine.94... 

The enolates of other carbonyl compounds can be used in mixed aldol reactions. Extensive use has been made of the enolates of esters, thiol esters, amides, and imides, including several that serve as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, titanium, and tin derivatives have all been widely used. The silyl ethers of ester enolates, which are called silyl ketene acetals, show reactivity that is analogous to silyl enol ethers and are covalent equivalents of ester enolates. The silyl thioketene acetal derivatives of thiol esters are also useful. The reactions of these enolate equivalents are discussed in Section 2.1.4. 

The highly ordered cyclic TS of the D-A reaction permits design of diastereo-or enantioselective reactions. (See Section 2.4 of Part A to review the principles of diastereoselectivity and enantioselectivity.) One way to achieve this is to install a chiral auxiliary.80 The cycloaddition proceeds to give two diastereomeric products that can be separated and purified. Because of the lower temperature required and the greater stereoselectivity observed in Lewis acid-catalyzed reactions, the best diastereoselectivity is observed in catalyzed reactions. Several chiral auxiliaries that are capable of high levels of diastereoselectivity have been developed. Chiral esters and amides of acrylic acid are particularly useful because the auxiliary can be recovered by hydrolysis of the purified adduct to give the enantiomerically pure carboxylic acid. Early examples involved acryloyl esters of chiral alcohols, including lactates and mandelates. Esters of the lactone of 2,4-dihydroxy-3,3-dimethylbutanoic acid (pantolactone) have also proven useful. 

The C(9)-C(14) segment VI was prepared by Steps D-l to D-3. The formation of the vinyl iodide in Step D-3 was difficult and proceeded in only 25-30% yield. The C(15)-C(21) segment VII was synthesized from the common intermediate 17 by Steps E-l to E-6. A DDQ oxidation led to formation of a 1,3-dioxane ring in Step E-l. The A-methoxy amide was converted to an aldehyde by LiAlH4 reduction and the chain was extended to include C(14) and C(15) using a boron enolate of an oxazo-lidinone chiral auxiliary. After reductive removal of the chiral auxiliary, the primary alcohol group was converted to a primary iodide. The overall yield for these steps was about 25%. 

Isolated polynucleotide clusters from Rhodococcus opacus which encode four polypeptides possessing the activities of a NHase (a and /3 subunits), an auxiliary protein P15K that activates the NHase, and a cobalt transporter protein were expressed in Escherichia coli DSM 14459 cells [34]. Methionine nitrile was added continuously to a suspension of the transformant cells (5.6% w/v of wet cells) in phosphate buffer (50 mM, pH 7.5) at 20 °C, at a rate where the nitrile concentration did not exceed 15 g L 1 while maintaining the pH constant at 7.5. After 320 min, the nitrile was completely converted into amide, corresponding to a final product concentration of 176 gL1.4-Methylthio-a-hydroxybutyramide is readily hydrolyzed with calcium hydroxide, where the calcium salt of 4-methylthio-a-hydroxybutyric acid (MHA) can be directly used as a nutritional supplement in animal feed as an alternative to methionine or MHA. 

L-tryptophan is compulsory, the biosynthetic machinery displays wide latitude in its ability to condense a second auxiliary amino acid—L-alanine in the case of (+)-ll,ll -dideoxyverticillin A (1)—to afford a tryptophan-derived diketopiperazine intermediate 13. Mirroring Woodward and Robinson s biogenetic hypothesis for the calycanthaceous alkaloids, single-electron oxidation of the electron-rich tryptophan residue would likely initiate an oxidative dimerization of the diketopiperazine precursor with concomitant cyclization to yield the octacyclic intermediate 17. Subsequent A-methylation of the amides would then yield an unembellished skeletal core of the dimeric epipolythiodiketopiperazine alkaloids. The first step en route... 

Reagent control This involves the addition of a chiral enolate or allyl metal reagent to an achiral aldehyde. Chiral enolates are most commonly formed through the incorporation of chiral auxiliaries in the form of esters, acyl amides (oxazolines), imides (oxazolidinones) or boron enolates. Chiral allyl metal reagents are also typically joined with chiral ligands. 

As with the above pyrrolidine, proline-type chiral auxiliaries also show different behaviors toward zirconium or lithium enolate mediated aldol reactions. Evans found that lithium enolates derived from prolinol amides exhibit excellent diastereofacial selectivities in alkylation reactions (see Section 2.2.32), while the lithium enolates of proline amides are unsuccessful in aldol condensations. Effective chiral reagents were zirconium enolates, which can be obtained from the corresponding lithium enolates via metal exchange with Cp2ZrCl2. For example, excellent levels of asymmetric induction in the aldol process with synj anti selectivity of 96-98% and diastereofacial selectivity of 50-200 116a can be achieved in the Zr-enolate-mediated aldol reaction (see Scheme 3-10). 

---