Sultams amides

Fig. 2 Preparation of 1 via chiral sultam amide 9. Route A (a) allylbromide, K2C03 (b) 220°C (c) KOH (d) 0s04, Nal04 (e) TsOH, benzene (f) NaOH, EtOH, heat (g) H2, Pd/C (h) LAH (i) Swern oxidation ...

Route A (chiral sultam amide) Route B (resolution with DAA) Route C (epoxide) Route D (asymmetric cyclopropanation)... 

An ingenious application was in the asymmetric synthesis of coniine15 114, the alkaloid in hemlock by which Socrates met his death. The sultam amide 111 incorporates a protected ketone so that acidic hydrolysis forms the cyclic nitrone 112 by capture of that ketone. Reduction and base-catalysed cleavage of the amide gives coniine 114. 

A highly stereoselective synthesis of the (3-substituted P-amino sulfone 271 involves the addition of a sulfonyl anion, derived from A-PMB sultam 268 upon treatment with NaHMDS, to chiral A-sulfinyl imine (5)-269 <06OL789>. Removal of the A-sulfinyl followed by basic workup affords amine 271. The stereochemical outcome of the adduct 270 was established via proton NMR analysis of the Mosher s amide derived from 271. 

The a,p-unsaturated amides 180-188a have all been used in 1,3-dipolar cycloadditions with nitrile oxides, and some of them represent the most diastereoselective reactions of nitrile oxides. The camphor derivative 180 of Chen and co-workers (294), the sultam 181 of Oppolzer et al. (295), and the two Kemp s acid derived compounds 186 (296) and 187 (297) described by Curran et al. (296) are excellent partners for diastereoselective reactions with nitrile oxides, as very high diastereos-electivities have been observed for all of them. In particular, compound 186 gave, with few exceptions, complete diastereoselection in reactions with a wide range of different nitrile oxides. Good selectivities were also observed when using compounds 183 (298) and 184 (299-301) in nitrile oxide cycloadditions, and they have the advantage that they are more readily available. Curran and co-workers also studied the 1,3-dipolar cycloaddition of 187 with silyl nitronates. However, compared to the reactions of nitrile oxides, lower selectivities of up to 86% de were obtained (302). 

Amides prepared from both enantiomers of 10,10-dimethyl-4-aza-3-thiatricyclor5.2.1.01,5ldecane 3,3-dioxide (bornane-10,2-sultam) can be used in diastereoselective alkylation reactions to give high chemical yields and high diastereomeric ratios of monoalkylation products5,6,10,16-19. 

Utilization of a,(3-unsaturated amides derived from the chiral amine, namely, camphor sultam, has been made by several groups to test the feasibility of [l,3]dipolar cycloaddition reactions with these chiral systems. This methodology has been applied to the synthesis of (35,4/ )ethyl-l-azabicyclo[2.2.1]heptane-3-carboxylate (see above for non-specific syntheses).433... 

Simple modifications of the ester group of 3-carboxyalkyl /3-sultams can be achieved and aminolysis furnishes the corresponding amides while reduction leads to the corresponding alcohol (Scheme 35) <2004HCA90>. 

Asymmetric versions of this fundamental way of making carbon-carbon bonds have attracted considerable attention lately. The diastereoselective version has proven successful in terms of high inductions and versatility of the substrate (unsaturated ketones, esters, amides, sultames, oxazolidines, aldimines. ..). The very large amount of data reported in this area precludes its coverage but excellent reviews are available143-145. The fine example displayed below, in which the intermediate enolate is trapped intramolecu-larly, illustrates the potency of this approach (Scheme 31)146. Similarly, good results were obtained with lithium enolates derived from (—)-8-phenylmenthyl esters147. 

Stereoselective formation of carbocycles has been carried out through [RhCl(cod)]2 (cod = cyclooctadiene) catalyzed reaction of alkenylzirconocene chloride to co-carbonyl carboxymide <07TL6471>. When the camphor sultam auxiliary is incorporated into amide 206, the Rh(I)-catalyzed reaction of alkenylzirconocene chloride 207 forms the cyclization product 211 with high diastereoselectivity. The tt-facial differentiation of the double bond in 206 for the initial attack of vinyl group can be explained by taking into consideration either of the reactive conformers A or B. No matter which reactive conformer is involved, the attack of the vinyl group to the less crowded C p si-face would account for the observed chirality. 

Camphor-10-sulfonic acid (1) is available in large quantities in both enantiomeric forms. In only 3 steps the cyclic sulfonamide 2 (sultam) can be synthesized, which can be acylated with acid chlorides after deprotonation with sodium hydride (Scheme 1) [1, 2]. The resulting amides 3 are considerable more reactive towards nucleophiles than the corresponding carboxylic esters and the a,/ -unsaturated derivatives undergo, with excellent selectivities, Diels-Alder reactions or Michael additions under mild conditions. Al-... 

Acryloyl and crotonoyl amides (9) derived from the sultam (8), available from ( + )-l, are somewhat more reactive dienophiles than the i orresponding esters (3) derived from 2. Diels-Alder reactions of 9 with cyclopentadiene catalyzed by TiCU or C2H,AIC1, proceed in high yield, with high endo selectivity ( 99%) ind diastereoselectivity of —95% de. The chiral auxiliary is removed by reduction witfi LiAIH4 to furnish 8 and the chiral alcohol in 89-95% yield.-... 

Asymmetric Alkylations. The use of nitrogen derivatives of carbonyl compounds (imines, imides, amides, sultams, oxazo-lines) is often the most efficient procedure for achieving a-alkylations. Chiral auxiliaries bearing heteroatoms in a 1,2-relationship appear to work best, as they have chelation sites for the metal cation. High levels of asymmetric induction can thus be achieved due to the system rigidity. Cyclic ketones have been alkylated via the lithiated enamine formed from L-f-leucine f-butyl ester (eq 1). High enantiomeric excesses and predictability of absolute configuration make this method attractive. 

Enantioselective intramolecular amidation with in tf/ -generated phenyliodinanes, derived from several alkane-sulfonamides, can be carried out affording cyclization products but in quite variable yields. Formation of six-membered sultams 419 ( = 2) was preferred over the five-membered derivatives 419 ( = 1). Good yields but low selectivity in the formation of the corresponding benzosultams was achieved with benzenesulfonamides 420 <2004HCA1607>. 

Oppolzer s (2/ )-bornane-10,2-sultam 150 is a good auxiliary that transmits its chirality to the a-carbon of an amide. The reaction of lithium enolate of 151 with the corresponding... 

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