Sultams auxiliaries

Fig. 6. Preparation of Oppol2er s chiral sultam auxiliary (85) and use of this chiral auxiUary for the preparation of t-phenylalanine.

Entry 3 involves another sultam auxiliary. The chirality of the product is consistent with approach of the diene from the re face of a conformation in which the carbonyl oxygen is syn to the sulfonyl group. 

Further examples of the endocychc nitrone route to spirocychc adducts are the total syntheses of (—)-histrionicotoxin (230) by Holmes and of cyhndricines by Weinreb. Histrionicotoxin is one of many spiropiperidine alkaloids isolated from the poison-arrow frog Dendrobates histrionicus and has been the subject of many attempted total syntheses by a nitrone cycloaddition strategy that failed to provide the desired regioisomer, possibly through unfavorable steric interactions (265-268). Unlike these reports, Holmes and co-workers (101) found that the intermolecular reaction of nitrone (231), prepared by the 1,3-APT of the corresponding alkynyl-hydroxylamine carrying Oppolzer s chiral sultam auxiliary, afforded the styrene... 

As noted previously, the use of chiral sultam auxiliaries provides access to ena-ntiomerically enriched isoxazolines. These products can be elaborated to provide nonactic acid and 8-ep/-nonactic acid, the subunits of nonactin (Scheme 2.15) (141-143). Subsequent cleavage of the isoxazoline ring in the presence of Raney... 

Oppolzer s camphor sultam, a well known chiral auxiliary, has been applied to the asymmetric synthesis of chial fluorine-containing amino acids <07OL2513>. Photoinduced addition of perfluoroalkyl iodides 189 to /V-acyloylcamphorsultam 188 in the presence of an aqueous solution of sodium sulfite provides alkyl iodides 190 with moderate to good stereoselectivities. Azide displacement with the major diastereomer of 190 proceeds with inversion of configuration. Subsequent removal of the sultam auxiliary and hydrogenation of the azide afford the chiral fluorine-containing amino acid 192. 

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. 

One of the most notable properties of sultam-modified substrates is that they undergo highly selective reactions in Lewis-acid-catalyzed as well as in thermal processes. There are a number of investigations into the basic selection mechanisms of the sultam auxiliary [5], which were carried out mainly by the groups of W. Oppolzer and D. Curran. In summary, the following model has arisen, which is described here giving the... 

Syn-, anti- and acetate aldol derivatives can be synthesized by choosing appropriate enolization protocols (Scheme 5) [20]. With lithium, boron and tin Lewis acids,. tyn-aldols can be obtained via (Z)-enolates [21]. If enolization is carried out with lithium or tin, there are enough open coordination sites available to position the aldehyde and the enolate in accordance with the chelate model for the sultam auxiliary and with the Zim-mermann-Traxler model. The combination of these models predicts the formation of 22, which is indeed experimentally obtained. If Lewis acids with only two open coordination sites are used... 

The asymmetric synthesis of (—)-denticulatin A (30) shows an interesting application of the boron aldol chemistry (Scheme 6) [23]. In a group-selective aldol reaction between the weso-aldehyde 27 and (5)-28, the hydroxyalde-hyde 29 was formed with > 90 % de, which spontaneously cyclized to the lactol 31. The configuration at the stereocenters of C-2 and C-3 in 29 is in accordance with the induction through the sultam auxiliary as well as with preference of an a-chiral aldehyde to react to the ant/-Felkin diastereomer in an aldol reaction which is controlled by the Zimmermann-Traxler model [24, 25]. 

Without doubt, with the discovery of the sultam auxiliaries W. Oppolzer has earned himself a place in the hall of fame of chemistry. With this contribution he will never be forgotten, even by people who, like the author of this article, have never had the chance to meet him personally. 

Tandem radical addition-aldol-type reaction of a,/3-unsaturated oxime ethers bearing an Oppolzer sultam auxiliary leads to stereoselective incorporation of alkyl groups in the 5- and 3-positions in tetrahydrofurans (Scheme 77) <2005AGE6190>. The observed /ra r,/ra r-stereoselectivity was explained by invoking a cyclic six-membered ring transition state. 

Scheme 101 Double asymmetric induction with the camphor sultam auxiliary...

Similar chemistry using chiral sultam auxiliaries demonstrates superior yields and selectivities for specific cases of cuprate conjugate additions, but have not yet been extended to the more complex multistep transformation series illustrated above. Moderate selectivities have been obtained in alkyl cuprate additions to y-aminocrotonate equivalents where the nitrogen is derived from the oxazolidinone. ... 

Nondestructive Auxiliary Cleavage. One feature which makes the sultam chiral auxiliary, and to an even greater extent the related toluene-2,ot-sultam auxiliaries (see a-Methyltoluene-2,a-sultam), so versatile is the ease with which N-acyl bond fission occurs in derivatives. A great variety of extremely mild, bimolec-ular and intramolecular nondestructive cleavage protocols have been developed which tolerate a wide array of molecular functionality, simple extraction and crystallization usually providing almost quantitative auxiliary recovery without loss of enantiomeric purity. 

Nondestructive Auxiliary Cleavage. The toluene-2,a-sultam auxiliaries are even more readily cleaved from derivatives than the 10,2-camphorsultam auxiliary. Following iV-acyl bond cleavage, simple extraction and crystallization usually effect almost quantitative recovery of enantiomerically pure auxiliary which may be re-used if desired. 

The a-methyltoluene-2,a-sultam auxiliary is also displaced by a variety of dilithiated alkyl phenyl sulfones. This unique procedure provides direct access to synthetically useful p-oxo sul-fones which may be further functionalized or simply subjected to reductive desulfonation to give alkyl ketones. A particularly strik-... 

A copper-catalyzed 1,4-addition was also described by Oppolzer and Kingma [39], Addition of the Grignard to an enoylsultam [Eq. (10)] could possibly product four products because two stereogenic centers are formed. The authors found a high yield (90%) of a mixture of diastereomeric pairs, identified after in situ hydrolysis to recover the sultam auxiliary. The major products were the S,S- and the R,R-diastereomers (86 12). The authors rationalize the differences in the observed stereochemistries by coordination of the magnesium and copper with the carbonyl and the oxygens of the sultam, thereby permitting addition to the Re-face. 

The sulfur ylides 254 used in the stereoselective [2,3]-sigmatropic rearrangement are generated by copper(I)-catalyzed Doyle-Kirmse reaction of aryl sulfides 253 and diazo compounds bearing Oppolzer s camphor sultam auxiliary 252 in the presence of chiral diamine ligand S, S)-259 <05JA15016>. These intermediate ylides undergo spontaneous... 

Acyclic dienes bearing Oppolzer s sultam auxiliary 261 have been utilized in the synthesis of functionalized 1,4-dihydronaphthalenes <05JA15028>. Cycloaddition of dienes 261 with benzynes, generated from 2(trimethylsilyl)phenyl triflate 263 using cesium fluoride, provides cycloadducts 263 with excellent diastereoselectivities. 

A highly diastereoselective 1,3-dipolar cycloaddition of a nitrone employing the sultam auxiliary has been used in the synthesis of 215, a major metabolite of nicotine <04T9997>. i-gulose-derived nitrone 212, upon treatment with a, P-unsaturated sultam (25)-213, undergoes 1,3-dipolar cyeloaddition to afford the isoxazolidine 214 with high endo stereoselectivity, which is further elaborated to hydroxycotinine (-i-)-215. 

The radical addition to 4 has been used as a basis for the synthesis of amino acids. Thus, the isopropyl radical adduct 5 has been converted to the amino acid 8 by reductive removal of the benzyloxy group of the major diastereomer R-5 by treatment with Mo(CO)6. Subsequent removal of the sultam auxiliary by standard hydrolysis afforded the enantiomerically pure D-valine without any loss of stereochemical purity. A variety of alkyl radicals were employed in the addition reaction, which gave the alkylated products with excellent diastereoselectivity, allowing access to a wide range of enantiomerically pure natural and unnatural amino acids. Even in the absence of Bu3SnH, treatment of 4 with alkyl iodide and EtsB at 20 °C gave the C-alkylated products with moderate diastereoselectivities. The use of... 

Highly selective Diels-Alder reactions with other chiral auxiliaries attached to the dienophile have been documented. For example, chiral 2-oxazolidinones or the camphor sultam auxiliaries have proven particularly useful. Such cycloaddition reactions, catalysed by an alkylaluminium chloride, occur with a variety of dienes to give adducts in high yield and with very high diastereoselectivity. In many cases these adducts can be obtained diastereomerically pure by crystallization. The reactions are thought to occur by way of complexed ion pairs (e.g. 129), in which the substituent on the auxiliary shields one face of the dienophile from attack by the diene. For example, 2-methylbutadiene (isoprene) gave the adduct 127, which was converted into (i )-(+)-a-terpineol 128 (3.92). ... 

Chelation is also thought to play an important part in directing the facial selectivity of cycloadditions with the camphor sultam auxiliary. A variety of dienes can be used and adducts are obtained with very high diastereomeiic excesses. Both inter-and intramolecular cycloaddition reactions are amenable to the use of a chiral auxiliary. An intramolecular example is illustrated in Scheme 3.93, in which the diene and dienophile are tethered and in which cycloaddition leads to predominantly one of the two diastereomeric trans-fusQd bicyclic (endo) products. The dienophile is thought to adopt the s-cis conformation, with the aluminium atom complexed to the carbonyl and one of the two sulfone oxygen atoms. 

The camphor sultam auxiliary 63 was removed with L-Selectride. 

TABLE 2. Cyclopropanation of a,/3-unsaturated amides modified by the sultam auxiliary with diazomethane... 

Nondestructive Auxiliary Cleavage. The toluene-2,a-sultam auxiliaries are even more readily cleaved from derivatives than the... 

The a-methyltoluene-2,o -sultam auxiliary is also displaced by a variety of dilithiated alkyl phenyl sulfones. This unique procedure provides direct access to synthetically useful fi-o o sul-fones which may he further functionalized or simply subjected to reductive desulfonation to give alkyl ketones. A particularly striking use of this method is the preparation of p-oxo sulfone 8, a key intermediate in a concise synthesis of (—)-semicorole (eq 5). Remarkably, the MeCLi2S02Ph reagent attacks selectively the C(4)-imide C=0 group in preference to the C(6)-ester C=0 group and no epimerization occurs at C(3) or C(F). 

After reductive cleavage of the N-0 bond in the presence of Mo(CO)6, and removal of the sultam auxiliary with LiOH in THF-H2O solution, various allylglycines were obtained with enantioselectivities ranging from 62 to 98% (Hanessian and Yang, 1996). 

Due to the high crystallinity of the sultam auxiliary, however, the aldol adducts 278 were obtained as nearly pure diastereomers after flash chromatography and recrystallization. The cleavage from the auxiliary by means of lithium hydroxide and hydrogen peroxide yielded the corresponding p-hydroxycarboxylic acids. The stereochemical outcome was rationalized by postulating an open transition state model 277, wherein the front side is shielded by the sulfonyl moiety so that the... 

The phosphodiesterase (PDE) IV inhibitor (109, Scheme 2.17) has been identified by Merck Research Laboratories as a potential lead for the treatment of asthma. Although an early synthesis of 109 relied on the use of Oppolzer s chiral sultam auxiliary, a more economic approach was subsequently developed that exploited an aminoindanol auxiliary. In the revised synthesis, the car-boxyhc acid 103 (available in two steps from isovanillin) is coupled with (15,2/ )-cis -aminoindanol 12 and subsequently converted into the amide 104. After protection of the amino alcohol, reaction of the resulting Michael acceptor 106 with phenyllithium 107 and subsequent... 

Multiple methods have been used to remove the sultam auxiliary after alkylation, none of which have been reported to cause epimerization at the newly formed stereogenic... 

Lin J, Chan WH, Lee AWM, Wong WY. Asymmetric alkylation mediated by tricyclic chiral sultam auxiliaries. Tetrahedron 1999 55 13983-13998. 

Oppolzer W, Rodriguez I, Starkemann C, Walther E. Chiral toluene-2,alpha-sultam auxiliaries—asymmetric alkylations, acylations and aldolizations of N-acyl derivatives. Tetrahedron Lett. 1990 31 5019-5022. 

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