Methyltoluene-2,a-sultam

Hashimoto, S. Kase, S. Shinoda, T. Ikegami, S. Chem. Lett. 1989, 1063. 

Kawamura, K. Ohta, X Otani, G. Chem. Pharm. Bull. 1990,38, 2088. 

Preparative Methods both enantiomers of the a-methyl sultam may be prepared on a multigram scale in optically pure form by asymmetric hydrogenation of imine (2a) followed by simple crystallization (eq 1). The (7 )-enantiomer of the a-f-butyl sultam may also be prepared in enantiomerically pure form by asymmetric reduction of imine (2b) followed by fractional crystallization. However, multigram quantities of either enantiomer of the a-t-butyl sultam may be prepared by derivati-zation of the racemic auxiliary (obtained in 98% yield from reaction of (2b) with Sodium Borohydride in MeOH) with 10-Camphorsulfonyl Chloride, separation of the resulting diastere-omers by fractional crystallization, and acidolysis. Prochi-ral imines (2a) and (2b) are readily prepared from inexpensive Saccharine by treatment with Methyllithium (73%) and t-Butyllithium (66%), respectively. 

Handling, Storage, and Precautions these auxiliaries are white crystalline solids which are stable indefinitely at ambient temperature in sealed containers. 

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. V-Enoyl and V-acyl sultam derivatives are readily prepared using either sodium hydride-acid chloride or triethylamine-acid chloride single-step protocols. Various alternative derivatization procedures that work for the 10,2-canphorsultam auxiliary would also be expected to be effective. 

Dienophile Diene Lewis acid Temp. (°C) Time (h) Adduct Yield crude (cryst.) (%) de crude (cryst.) (%) 

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Related Reagents. 10-Dicyclohexylsulfonamidoisobotneol (S)-Ethyl Lactate 3-Hydroxyisobomeol a-Methyltoluene-2,a-sultam. 

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. 

Dicyclohexylsulfonamidoisobomeol Diisopinocampheyl-boron Trifluoromethanesulfonate a-Methyltoluene-2,a-sultam 1,1,2-Triphenyl-1,2-ethanediol. 

Diels-Alder Cycloadditions (AUcene -+ Six-Membered Cycloadduct). lV-Acryloyl-a-methyltoluene-2,a-sultam (3a) participates in highly endo and C(a)-re ir-face selective Lewis acid promoted Diels-Alder reactions with Cyclopentadiene, 1,3-Butadiene, and Isoprene (eq 2 and Table 1). These levels of induction compare favorably with most alternative auxiliaries, including the 10,2-camphorsultam. However, V-crotonyl-a-methyltoluene-2,a-sultam (ent-3b) reacts with cyclopentadiene with only mod-... 

Dipolar Cycloadditions with Nitrile Oxides (Alkene-+-Isoxazoline) 1,3-Dipolar cycloaddition reactions of N-acryloyl-a-t-butyltoluene-2,a-sultam (6) with various nitrile oxides give isoxazolines with extremely high C(a)-re rr-facial control (eq 3). The levels of selectivity exceed those obtainable with the 10,2-camphorsultam auxiliary and are comparable to the highest levels reported for such cycloadditions. The corresponding reactions of a-methyltoluene-2,a-sultams are less selective. 

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. 

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-... 

Related Reagents. (S)-4-Benzyl-2-oxazolidinone 10,2-Camphorsultam (/ )-(+)-f-Butyl 2-(p-Tolylsulfinyl)propionate 10-Dicyclohexylsulfonamidoisobomeol Diisopinocampheyl-boron Trifluoromethanesulfonate (R,R)-2,5-Dimethylborolane 2,6-Dimethylphenyl Propionate Ethyl 2-(Methyldiphenylsilyl)-propanoate a-Methyltoluene-2,a-sultam 3-Propionylthiazoli-dine-2-thione (/ ,/ )-1,2-Diphenyl-1,2-diaminoethane iV,iV -Bis-[3,5-bis(trifluoromethyl)benzenesulfonamide] 1,1,2-Triphenyl-1,2-ethanediol. 

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