Sultams, acyl

In addition to the asymmetric induction mentioned above, sultam 53 can also be used to prepare enantiomerically pure amino acids (Scheme 2-29 and Table 2-10).55 Me AI-mediated acylation of 53 with methyl A-[bis(methylthio)-methylene]glycinate 56 provided, after crystallization, glycinate 57, which can serve as a common precursor for various a-amino acids. In agreement with a kinetically controlled formation of chelated (Z)-enolates, alkylation happened from the SZ-face of the a-C, opposite to the lone pair electrons on the sultam nitrogen atom. High overall yield for both the free amino acid 58 and the... 

Figure 4.7. Acylated Oppolzer s sultam 66 and proposed Zr-chelate intermediate 67.

The use of chiral A-acylated sultams 1 as auxiliaries for diastereoselective alkylation and related reactions has emerged as a useful and versatile method for the construction of chiral compounds. Both enantiomers of 10.10-dimethyl-4-a2a-3-thiatricyclo[S.2.1,0 -5]decane 3,3-dioxide (bomane-10,2-sultam) have been employed1-6 and are now commercially available. A chiral sultam prepared from saccharin has also been used for a variety of asymmetric transformations8,9. 

V-Acylbornane-l 0,2-sultams 2 are prepared from the bornane-10,2-sultam 1 via NH-deproto-nation with sodium hydride and subsequent acylation with a suitable acid chloride. 

Removal of the auxiliary is straightforward and consists of treatment of the alkylated A -acyl-sultam 5 with an excess of lithium hydroxide/30% hydrogen peroxide in tetrahydrofuran. Other mild cleavage methods are available20. 

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-... 

Also for stereoselective radical reactions such as radical additions or radical cyclizations, the camphor sultam 2 is suitable as an auxiliary (Scheme 7). The acyl radical which was gener-... 

The diastereoselective and enantioselective [2+2] cycloaddition of a 7-oxanorbornene with a chiral alkynyl acyl sultam was effected by using a ruthenium catalyst to provide the . 

In a series of papers24a c, Oppolzer et al. introduced another procedure for the enantioselec-tive amination of enolates based on the A-acyl camphor sultam 1 as a chiral template and 1-chloro-l-nitroso cyclohexane (2) as electrophile. 

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. 

Introduction. The toluene-2,a-sultams are recently introduced relatives of the well established 10,2-Camphorsultam chiral auxiliary and have been designed to provide similar high levels of face discrimination in reactions of pendent prochiral functionality. Feamres that distinguish them include high crystallinity and facile NMR and HPLC analysis of derivatives, favorable acylation and aldolization characteristics of derived Al-acyl enolates, and improved cleavage characteristics. 

Preparation of Derivatives. IV-EnoyP and IV-acyl sultam derivatives are readily prepared using either Sodium Hydride-acid chloride or Triethylamine-add chloride single-step protocols. Various alternative derivatization procedures that work for the 10,2-camphorsultam auxiliary would also be expected to be effective. 

Acylation, Alkylation, and Aldolization (Acyl Species-+ a-, P-, or a/fi-Functionalized Acyl Product) Alkylation reactions of sodium enolates of various lV-acyl-a-methyltoluene-2,a-sultams with selected (both activated and nonactivated ) alkyl iodides and bromides proceed with good C(a)-re stereocontrol (90-99% de). Analogous acylations with various acid chlorides can also be performed, giving p-keto products (97-99% de). Selective reduction of these latter products with Zinc Borohydride (chelate controlled, 82.6-98.2% de) or N-Selectride (nonchelate controlled, 95.8-99.6% de) can provide syn- and anft-aldol derivatives, respectively. ... 

Syn-aldol derivatives may also be obtained directly from bo-ryl enolates of the same M-acyl-a-methyltoluene-2,a-sultams by condensation with aliphatic and aromatic aldehydes (eq 4). The high C(a)-it topicity of these reactions parallels but exceeds that when using the 10,2-camphorsultam auxiliary and is the result of an analogous transition state. It is noteworthy, however, that al-dolizations of a-methyltoluene-2,a-sultam derivatives generally proceed to completion with just a small excess of aldehyde (1-1.2 equiv, cf. 2-3 equiv when 10,2-camphorsultam mediated). This may be ascribed to the lack of acidic protons a to the SO2 group in the Saccharine-derived auxiliary. 

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. 

Bomane-10,2-sultam (362) and its antipode, accessible from inexpensive (+)- and (-)-camphorsulfonic acid in two simple operations, were introduced in 1984 and rank today among the most practical auxiliaries (Scheme 88). Both chirophore enantiomers are commercially available in kg quantities. Almost all of their A -acyl derivatives are stable and can be (1) readily purified by crystallization, (2) directly analyzed by H NMR and/or GC to determine their stereochemical purity, and (3) cleaved e.g. with UAIH4, LiOH, LiOOH, MeOMgl, etc.) under mild conditions without loss of the induced chirality and with excellent recovery of the auxiliary. 

Solid-phase synthesis of substituted pyrazolones 550 from polymer-bound /3-keto esters 549 has been described (Scheme 68) <2001EJ01631>. Trisubstituted pyrazole carboxylic acids were prepared by reaction of polymer-bound arylidene- or alkylidene-/3-oxo esters with phenylhydrazines <1999S1961>. 2-(Pyrazol-l-yl)pyrimi-dine derivatives were prepared by cyclocondensation of ethyl acetoacetate and (6-methyl-4-oxo-3,4-dihydropyrimi-din-2-yl)hydrazine with aromatic aldehydes <2004RJC423>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted-pyrazolin-5-ones <2002T3639>. Reactions of hydrazines with A -acetoacetyl derivatives of (45 )-4-benzyloxazolidin-2-one (Evans oxazolidinone) and (2R)-bornane-10,2-sultam (Oppolzer sultam) in very acidic media gave pyrazoles retaining the 3(5)-chiral moiety <1999S157>. 

In view of their importance in enantioselective reactions, many bornane sultams have been synthesized and characterized by MS. Their El mass spectra show molecular ions with low abundance or are absent. N-Substituted bornane sultams generally show the typical fragmentations of the substituents <2000THS(4)405>. 1-Alkyl-7-nitro-2,1-benzisothiazole 2,2-dioxides show elimination of an acyl radical from their molecular ions <1997EJS55>. 

For the general structural types of tetrahydroisothiazoles, see CHEC-II(1996) <1996CHEC-II(3)319> (see p. 351). Apart from some examples of sultams substituted on nitrogen and carbon atoms with alkyl groups, of importance is the equilibrium between A-alkyl-A-acyl sultam and the corresponding isothiazolidinium salt (see Section 4.05.6.4.3), the synthesis and reactivity of thia-l-azabicyclo[3.1.0]hexane A,A-dioxide 243 and its benzo derivative (see Sections... 

N-Arylated 1,3-propanesultams 236 (R =Ar, R = H) are efficiently prepared from a Pd-catalyzed cross-coupling reaction with different aryl bromides in the presence of Xantphos <2004TL3305>. N-Fluorinated (-l-)-camphorsultams 237 (X = H, Cl, OMe R = F) have been prepared the corresponding imine 16 and difluoro derivative 238 were formed as by-products. The use of 237 is reported in Section 4.05.12.1 <1998JOC9604>. The syntheses of Ar-(l-alkynyl)-Oppolzer s sultams are reported in Section 4.05.6.3.4. Many examples of acylated Oppolzer s sultams are reported in Section 4.05.12.1. 

Several dihydro- or tetrahydro-isothiazole derivatives are used mainly as chiral scaffolds in diastereoselective syntheses. Among these, Oppolzer s sultam 582 (R = H) has been the most frequently used when functionalized at nitrogen with different acyl residues. A method for the removal of this chiral auxiliary has been described <1998SL882>. 

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