(1S)-(1a; R = Me)

[130973-57-8]  · C8H9NO2S  · a-Methyltoluene-2,a-sultam  · (MW 183.25) (1R)-(1a)

[130973-53-4] (1S)-(1b; R = t-Bu)

[137694-01-0]  · C11H15NO2S  · a-t-Butyltoluene-2,a-sultam  · (MW 225.34) (1R)-(1b)


(chiral auxiliary: N-enoyl derivatives undergo highly stereoselective Diels-Alder reactions with cyclopentadiene2 and 1,3-dipolar cycloadditions with nitrile oxides;3 enolates of N-acyl derivatives participate in highly stereoselective alkylations, acylations, and aldolizations4)

Physical Data: (1a) mp 92 °C. (1S)-(1a) [a]20D -30.0° (c 1.21, CHCl3). (1R)-(1a) [a]20D +31.0° (c 0.6, EtOH). (1b) mp 129-130 °C. (1S)-(1b) [a]20D -53.9° (c 1.00, CHCl3). (1b) has been incorrectly assigned.3

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).5 The (R)-enantiomer of the a-t-butyl sultam may also be prepared in enantiomerically pure form by asymmetric reduction of imine (2b) followed by fractional crystallization.3 However, multigram quantities of either enantiomer of the a-t-butyl sultam may be prepared by derivatization 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 diastereomers by fractional crystallization, and acidolysis.3 Prochiral 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.


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. Features that distinguish them include high crystallinity and facile NMR and HPLC analysis of derivatives, favorable acylation and aldolization characteristics of derived N-acyl enolates, and improved cleavage characteristics.

Preparation of Derivatives.

N-Enoyl2,3 and N-acyl4 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-camphorsultam auxiliary would also be expected to be effective.

Reactions of N-Enoyl and N-Acyl Derivatives.

[2 + 4] Diels-Alder Cycloadditions (Alkene -> Six-Membered Cycloadduct).2

N-Acryloyl-a-methyltoluene-2,a-sultam (3a) participates in highly endo and C(a)-re p-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, N-crotonyl-a-methyltoluene-2,a-sultam (ent-3b) reacts with cyclopentadiene with only moderate p-face selectivity (cf. 93% de with 10,2-camphorsultam). Unusually high endo selectivity is observed for the non-Lewis acid-catalyzed reaction of sultam (3a) with cyclopentadiene but again the p-face selectivity is only moderate. The corresponding reactions of both a-t-butyl- and a-benzyltoluene-2,a-sultams are less selective.

1,3-Dipolar Cycloadditions with Nitrile Oxides (Alkene -> Isoxazoline).3

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 p-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.6 The corresponding reactions of a-methyltoluene-2,a-sultams are less selective.

Acylation, Alkylation, and Aldolization (Acyl Species -> a-, b-, or a/b-Functionalized Acyl Product).3

Alkylation reactions of sodium enolates of various N-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 b-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 anti-aldol derivatives, respectively.3

Syn-aldol derivatives may also be obtained directly from boryl enolates of the same N-acyl-a-methyltoluene-2,a-sultams by condensation with aliphatic and aromatic aldehydes (eq 4).3,7 The high C(a)-si topicity of these reactions parallels but exceeds that when using the 10,2-camphorsultam auxiliary and is the result of an analogous transition state.3 It is noteworthy, however, that aldolizations 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 N-acyl bond cleavage, simple extraction and crystallization usually effect almost quantitative recovery of enantiomerically pure auxiliary which may be re-used if desired.

Enantiomerically pure carboxylic acids are routinely obtained from N-acylsultams by Hydrogen Peroxide assisted saponification with Lithium Hydroxide in aqueous THF.2,4 Alternatively, transesterification can be effected under neutral conditions in allyl alcohol containing Titanium Tetraisopropoxide, giving the corresponding allyl esters which can be isomerized/hydrolyzed with Wilkinson's catalyst (Chlorotris(triphenylphosphine)rhodium(I)) in EtOH-H2O. This provides a convenient route to carboxylic acids containing base-sensitive functionality.8 Primary alcohols are obtained by treatment with L-Selectride (Lithium Tri-s-butylborohydride) in THF at ambient temperature.3

The a-methyltoluene-2,a-sultam auxiliary is also displaced by a variety of dilithiated alkyl phenyl sulfones.7,9 This unique procedure provides direct access to synthetically useful b-oxo sulfones which may be further functionalized or simply subjected to reductive desulfonation to give alkyl ketones. A particularly striking use of this method is the preparation of b-oxo sulfone (8), a key intermediate in a concise synthesis of (-)-semicorole (eq 5).7 Remarkably, the MeCLi2SO2Ph reagent attacks selectively the C(4)-imide C=O group in preference to the C(6)-ester C=O group and no epimerization occurs at C(3) or C(1).

Related Reagents.

10,2-Camphorsultam; 10-Dicyclohexylsulfonamidoisoborneol; 2-Hydroxy-1,2,2-triphenylethyl Acetate; (4S,5S)-4-Methoxymethyl-2-methyl-5-phenyl-2-oxazoline; (S)-4-Benzyl-2-oxazolidinone.

1. Ganem, B. Chemtracts-Org. Chem. 1990, 435.
2. (a) Oppolzer, W.; Wills, M.; Kelly, M. J.; Signer, M.; Blagg, J. TL 1990, 31, 5015. (b) Oppolzer, W.; Seletsky, B. M.; Bernardinelli, G. TL 1994, 35, 3509.
3. Oppolzer, W.; Kingma, A. J.; Pillai, S. K. TL 1991, 32, 4893.
4. Oppolzer, W.; Rodriguez, I.; Starkemann, C.; Walther, E. TL 1990, 31, 5019.
5. Oppolzer, W.; Wills, M.; Starkemann, C.; Bernardinelli, G. TL 1990, 31, 4117.
6. Curran, D. P.; Jeong, K. S.; Heffner, T. A.; Rebek, J., Jr. JACS 1989, 111, 9238.
7. Oppolzer, W.; Rodriguez, I. HCA 1993, 76, 1275.
8. Oppolzer, W. Lienard, P. HCA 1992, 75, 2572.
9. Oppolzer, W.; Rodriguez, I. HCA 1993, 76, 1282.

Alan C. Spivey

University of Cambridge, UK

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