Synthesis of Sultams

Recently, Qian and Dong disclosed a highly efficient Rh-catalyzed three-component reaction of imines, alkynes, and aldehydes via C-H activation to afford highly fused polycyclic sultam skeletons [24]. This strategy allows the formation of four new bonds in a simple-to-perform, single-operation cascade of C-H activation/C=N insertion, C-H activation/C=0 insertion, and cyclization (Eq. (5.39)). 

Another approach to the construction of benzofused sultams was also reported by Wang and Li groups [25]. The reaction provides a wide scope of ort/zo-alkylated benzofused sultam analogs in good yields (Eq. (5.40)). The Af-acetyl group is important for rhodacycle formation and subsequent Michael addition reaction, which was finally removed under mild conditions to provide free NH sultams. 

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Cycloaddition reactions of heterocumulenes have been much used in the synthesis of / -sultams. The two general methods, emphasizing different synchronous bond formations, are outlined in equations 198 and 199. 

To address the problems of slow cleavage kinetics and methionine oxidation associated with the use of photolabile support Ij (Table 1), a linker based o -methyl-6-nitroveratryl alcohol [227,228] was designed. The additional ring alkoxy groups and the a-methyl group of support 5q facilitate cleavage and lead to fewer side products that result from the photoproduct, a resin-bound nitroso ketone, compared with Ij and other conventional photolabile linkers. Support 5q has been used for the synthesis of sultams [229], which were cleaved from the resin by irradiation in 2-propanol at 365 nm. 

Scheme 8.123 Synthesis of sultams via intermolecular aminoarylation of aliphatic alkenes.

SCHEME 30.40. Pd-Catalyzed enantioselective hydrogenation of ALsulfonylimine 206 in the synthesis of sultam with anti-HIV activity. 

Yu C-B, Wang D-W, Zhou Y-G. Highly enantioselective synthesis of sultams via Pd-catalyzed hydrogenation. J. Org. Chem. 2009 74(15) 5633-5635. 

Cava and Schlessinger have reported the synthesis of 1,2,3-triphenyl-isoindole (65) in 78% yield from 1,3-diphenylisobenzofuran (68) hy reaction with thionylaniline (69) and boron trifluoride. The mechanism proposed for this remarkable transformation involves reaiTangement of the adduct (70) derived from thionylaniline and the isobenzofuran, to the tricyclic intermediate (71). This presumably collapses to the S-sultam (72), which yields the isoindole (65) upon extrusion of sulfur dioxide. Loss of sulfur dioxide, both from S-sultones and unsaturated S-sultams, is well documented. ... 

The first synthesis of stable 3-hydroperoxy-sultams (24) which are a new class of sultam with oxidising properties, was reported. The synthesis involved oxidation of the isothiazolium salts (23) with hydrogen peroxide in acetic acid. Reduction of (24) with aqueous sodium bisulphite afforded the corresponding novel 3-hydroxysultams whereas thermolysis in ethanol resulted in the elimination of water to give 3-ketone derivatives, which are versatile as dieneophiles <96T783>. 

Zajac M, Peters R (2009) Catalytic asymmetric synthesis of P-Sultams as precursors for taurine derivatives. Chem Eur J 15 8204-8222... 

The camphor sultam derivative 21A was used in a synthesis of epothilone. The stereoselectivity of the aldol addition was examined with several different aldehydes. Discuss the factors that lead to the variable stereoselectivity in the three cases shown. 

Hanessian reported the synthesis of enantiomerically pure or highly enriched allylglycine and its chain-substituted analogs from the reaction of the sultam derivatives of O-benzyl glyoxylic acid oxime with ally he bromides in the presence of zinc powder in aqueous ammonium chloride (Eq. 11.41).72 Brown noticed the critical importance of water in the asymmetric allylboration of /V-trimethylsilyIbcnzaldimines with B-allyldiisopinocampheylborane.73 The reaction required one equivalent of water to proceed (Eq. 11.42). 

A stereoselective one-pot synthesis of substituted 1,2-thiazetidine 1,1-dioxides (P-sultams) 55 started from heterocyclic pentafluorophenyl (PFP) sulfonates <06OL5513>. 

A practical synthesis of the bicyclic dienyl sultam 246 has been reported <06JOC6573>. The key step of the ring-closing metathesis (RCM) represented by conversion of 243 to 244 has to be implemented prior to the sultam formation (244 to 245). Bicyclic sultam is converted to dienyl sultam 246 in two steps. 

An efficient synthesis of A-alkylated-4-substituted isothiazolidine-dioxides (sultams) 251 has been developed utilizing epoxides 248 <06TL4245>. Addition of a secondary sulphonamide 247 to epoxide 248 in hot 1,4-dioxane affords the amino alcohol 249, which is... 

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. 

Stereochemical control of intramolecular 1,3-dipolar cycloadditions by route b (Scheme 2.211) was realized in the asymmetric synthesis of l-azaspiro[4.5] decanes by using the chiral (2R)-bomane-10,2-sultam (X ) auxiliary in the dipo-larophilic fragment (Scheme 2.220) (718). 

For a review of sultam chemistry, interested readers can refer to Oppolzer s article57 on Camphor as a Natural Source of Chirality in Asymmetric Synthesis. ... 

Camphor sultam derivatives have proved to be effective chiral auxiliaries in many different types of asymmetric reactions. As shown in Scheme 5-44, chiral camphor sulfam can be applied in the synthesis of (—)-pulo upone precursor 151 using an intramolecular Diels-Alder reaction. A Wittig reaction of 148 with 147 connects the chiral auxiliary to the substrate, and subsequent intramolecular Diels-Alder reaction via transition state 150 affords product 151. Compound 151 already has the stereochemistry of (—)-pulo upone 153.72... 

Four-membered ring adducts from 2n + 2n cycloaddition of keten-imines to sulfur dioxide. Isolation of l,2-thiazetidin-3-one 1-oxides. jS-Sultames. Simple method for synthesis of substituted 1,2-thia-zetidin 1,1-dioxide. ... 

Oppolzer et al. (321) applied his own sultam as the auxiliary for a cychc nitrone in the synthesis of (—)-allosedamine (Scheme 12.60). The enantiomerically pure nitrone 209 was synthesized from 208 by base treatment, attack of the enolate on 1-chloro-l-nitrosocyclohexane at the nitrogen atom, and subsequent elimination of chloride. Subsequent addition of aqueous HCl gave the cyclic nitrone 209. The nitrone participated in a 1,3-dipolar cycloaddition with styrene, proceeding with complete exo-specificity. The product, 210, was obtained with a de of 93%. Two further reaction steps yield the piperidine alkaloid ( )-aUosedamine 211 in an overall yield of 21%. 

More recently, this approach has been extended to the synthesis of chiral sultams such as 129, which have been employed as chiral auxiliaries for Diels-Alder reactions, for example. Equation (27) <2005TA761>. 

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