Chemistry Corner

Chiral chemistry with sulfur

Chiral sulfur compounds are finding use as effective catalysts and ligands for the asymmetric synthesis of valuable, complex intermediates, reports Dr Cynthia Challener

The need for new methods that facilitate the asymmetric synthesis of complex, functionalised compounds continues to grow. Research efforts have therefore expanded into new areas, including the development of chiral sulfur compounds as catalysts and ligands for enantioselective transformations. In some cases, the chirality is established in the structure of the molecule; in others, the sulfur atom itself is chiral.

The approach of Albert Lee at Hong Kong Baptist University involves the modification of widely used sulfur compounds in asymmetric synthesis, particularly camphor sulfonic acid (CSA), to prepare chiral sulfur organocatalysts. In this case, the chirality is derived from the camphor backbone. Both enantiomers of CSA are inexpensive and readily available in their pure forms. 

Cyclic camphor sulfonyl hydrazines (CaSHs) were readily prepared by converting CSA into the sulfonyl chloride via reaction with SOCl2 followed by cyclisation with hydrazine monohydrate and then treatment with acid. Various derivatives with substituents on the α and β nitrogens were then evaluated in the Diels-Alder reaction of cyclopentadiene with trans-cinnamyl aldehyde. 

Their α-N-alkyalted (benzyl or ethyl) derivatives gave good yields (up to 90% with 93% endo ee) when used with 0.1 eq. of trichloroacetic acid as a co-catylyst in water for 48 hours at 0°C. The ethyl camphor sulfonyl hydrazine derivative was also found to be effective for catalysing the asymmetric Aza-Michael addition of bis-Cbz-hydroxylamine to aliphatic α,β-unsaturated aldehydes in toluene at 0 to -10°C to produce amino alcohols with 88-90% ee.
 
More recently, Lee developed a newer generation catalyst starting from Oppolzer's camphor sultam. In this catalyst, the primary hydrazine functionality is external to the tricyclic structure and therefore exhibits higher reactivity. In fact, it activates ketones in asymmetric Diels-Alder reactions in the presence of added triflic acid in toluene at -20°C for 48 hours. Yields of ~70% with an endo:exo ratio of 98:2 and up to 96% ee can be obtained for a wide range of α-aryl substituted α,β-unsaturated ketones with different steric and electronic properties and several different dienes (Figure 1).
 
 
Figure 1 - Chiral sulfonyl hydrazine as organocatalyst for enantioselective Diels-Alder reactions
 
Lee also demonstrated that binaphthyl-based chiral sulfonimides (CSIs) act as efficient, strong Brønsted acids in the catalysis of asymmetric Friedel-Crafts alkylations of indoles. Washing the catalyst with HCl to remove metal impurities is critical for this reaction. When run in toluene at -40°C, it is complete in ten minutes and gives a 90% yield with 89% ee. At 0°C, the reaction proceeds in five minutes to give 88% yield and 77% ee. Electron-withdrawing groups on the indole led to reduced ee's, whilst electron-donating substituents improved the enantioselectivity.
 
Meanwhile, Varinder Aggarwal at the University of Bristol has been exploring organic transformations mediated by chiral sulfur ylides. Specifically, his group has developed a method for the selective asymmetric epoxidation and aziridination of alkenes. 
 
The chiral sulfide used in these reactions is prepared in one step from limonene, an inexpensive starting material with both stereoisomers available in reasonably high purity. Isothiocineole was prepared in a solvent-free reaction from limonene and elemental sulfur in the presence of γ-terpinene at 110°C. The pure product is obtained after distillation in 36% yield with 98% ee.
 
The benzylsulfoniumn salt of the chiral sulfide reacts with aldehydes at 0°C in the presence of KOH in acetonitrile and water or acetonitrile and tert-butanol solvent to give 1,2-arylalkyl epoxides in high diastereo- and enantioselectivity, with moderate to good yields. Allylic sulfonium salts bearing an α-substituent also work well to provide α,β-unsaturated epoxides.
 
The utility of this reaction was demonstrated through the convergent synthesis of the cinchona alkaloids quinine and quinidine, which are diastereomers of each other. Chiral epoxidation mediated by a chiral sulfide was the differentiating step for preparation of the two products. Aggarwal also showed that the benzylsulfonium salt effectively mediates aziridinations in the presence of K2CO3 in MeCN at room temperature (Figure 2). 
 
 
Figure 2 - Synthesis of quinine & quinidine via enantioselective sulfur ylide mediated asymmetric epoxidation
 
The value of the chiral vinyl aziridines produced in these chiral sulphide-mediated reactions was demonstrated in the synthesis of substituted pyrrolidines. Aggarwal employed a palladium-catalysed annulation of vinyl aziridines with Michael acceptors in this diastereoselective transformation, which he applied towards the concise synthesis of (-)-α-kainic acid.
 
The easy handling and stability of compounds with chirality at the sulfur atom have attracted the interest of other researchers. As a ligand for transition metals, the asymmetric sulfur atom may also provide a unique chiral environment at the metal centre to give high selectivities. 
 
Du Haifeng of the Institute of Chemistry and Xu Ming-Hua at the Shanghai Institute of Materia Medica, both of which are part of the Chinese Academy of Sciences, have independently discovered the effectiveness of N-sulfinamide-based chiral sulfur-olefin ligands in various asymmetric transition metal-catalysed reactions.
 
Chiral tert-butanesulfinamide is inexpensive and both enantiomers are readily available in pure form. It has been used in the past to prepare chiral ligands for asymmetric synthesis, but rarely has the sulfur atom of these ligands been intended to be the coordinating atom, even though the sulfur is chiral. Chiral olefin ligands have also attracted attention, but generally only phosphorus and nitrogen have been incorporated.
 
Both Du and Xu have developed ligands that incorporate the chiral tert-butanesulfinamide group and olefins to form N-sulfinyl-based chiral sulfur-olefin ligands in which the chiral sulfur atom coordinates to the metal. Du synthesised a range of ligands containing both terminal and internal olefins via the condensation of aromatic aldehydes with (R)-tert-butanesulfinamide, followed by addition to a vinyl Grignard reagent or reduction with DIBAL-H. The desired products were obtained in high yields and diastereoselectivities (many >99:1). 
 
The ligand was first tested in the rhodium-catalysed (5 mol%) 1,4-addition of phenylboronic acid to 2-cyclohexenone in the presence of K3PO4•3H2O in water at room temperature for three hours. The desired product was obtained in 99% yield and 92% ee. Control experiments confirmed that both the sulfinyl and olefin portions of the ligand are necessary for high enantioselectivity (Figure 3). 
 
 
 
Figure 3 - Asymmetric rhoidum catalysis using N-sulfinyl-based chiral sulfur-olefin ligands
 
Interestingly, ligands with internal olefins gave the opposite enantiomer as those with external double bonds, and the chiral purity at the carbon in the olefin had minimal impact on the selectivity and conversion. This indicates that the chirality at sulfur plays a crucial role in determining the outcome.
 
The two best ligands were found to incorporate 3-(4-methoxyphenyl)-1-propene and 1,3-diphenyl-1-propene as the olefinic portion, and were very effective for reactions between 2-cyclohexenone and para- or meta-substituted arylboronic acids, whilst ligands with internal olefin groups were more effective for the ortho-substituted derivatives and other enones, such as cyclopentenone, cycloheptenone and unsaturated furanones, and also with t-butyl cinnamate.
 
Since chirality on carbon had no apparent impact, Du extended the reaction to simpler ketimine ligands prepared via the condensation of α,β-unsaturated ketones with (R)-tert-butanesulfinamide. The same 1,4-addition proceeds with these ligands in quantitative yield with 97% ee when carried out in MeOH at 30°C for four hours. The ligand prepared from chalcone was found to exhibit the highest reactivity and enantioselectivity, particularly with the addition of CsF and use of higher catalyst loadings. Even linear enones gave the desired products with moderate ee's.
 
Next, Du extended the reaction to the 1,4-addition of phenylboronic acid to hindered Morita-Baylis-Hillman cyclopentenone adducts for the synthesis of nonactivated α,α,β-trisubstituted alkenes. In this case, the ligand structure strongly affected both the activity and selectivity of the reaction.
 
Conversions were low, but the recovered starting material was the R isomer with a high ee, indicating that kinetic resolution was occurring. The ligand with 1,3-diphenyl-1-propene as the olefinic portion gave the best results when 50 mol% KOH was used at 30°C. A conversion of 47% was achieved with high ee's for both the product and recovered starting material.
 
Xu, meanwhile, has also used chiral tert-butanesulfinylimine in the design and development of novel sulfur-olefin ligands for asymmetric catalysis and as a reagent for the asymmetric synthesis of various chiral amines. His group designed a range of easily accessed chiral N-sulfinylhomallylic amines (one step via simple allylation or benzoyloxyallylation of N-tert-butanesulfinylimine) as novel sulfinamide-olefin hybrid ligands for asymmetric catalysis. 
 
In the model rhodium-catalysed 1,4-addtion reaction of phenylboronic acid with 2-cycolexenone (with K3PO4 in dioxane), he found that using an aromatic N-tert-butanesulfinylhomallylic amine with a benzyloxy substituent on the allylic carbon as the chiral ligand and anthracene as the aromatic moiety provided a 99% yield with 95% ee for the addition product. 
 
The control experiments illustrated that reaction enantioselectivity was primarily controlled by the stereochemistry of the N-sulfinyl group. With the optimised catalytic system, a diverse range of boronic acids with different steric and electronic properties were shown to react well with cyclic enones, giving high yields and ee's up to 98%.
 
Xu also prepared ligands with the sulfinyl group and the olefin attached in the 1,2 position on the aromatic ring, from inexpensive starting materials in three steps, and evaluated their performance in the same model reaction. The best results - 99% yield and 97% ee - were obtained using a ligand with an internal olefin bearing a phenyl group and three methoxy substituents on the aromatic ring containing the sulfoxide and alkene groups. 
 
The reaction was carried out in THF with 0.5 equivalents of added K2HPO4, using two equivalents of boronic acid and 3 mol% catalyst at 60°C for 0.5 hours (Figure 4). A wide range of phenylboronic aicds with different steric and electronic demands and also different cyclic α,β-unsaturated carbonyl compounds are tolerated.
 
Most promisingly, highly enantioselective 1,2-additions of aryl boronic acids to α-ketoesters and α-diketones using these chiral sulfur-olefin ligands is also successful and provides optically active tertiary α-hydroxy carbonyl compounds with quaternary stereogenic centres.
 
Xu found that an extremely simple chiral N-(sulfinyl)cinnamylamine ligand (which can be prepared in a single-pot operation from cinnamaldehyde and chiral N-tert-butanesulfinamide) is effective for rhodium-catalysed reactions of aryl boronic acids with both α-ketoesters and α-diketones with high enantisoelectivity under mild conditions. 
 
Using [{Rh(coe)2Cl}2] (3 mol%) with added aqueous KOH (0.1 M) in THF at room temperature, the addition of p-tolylboronic acid to 2-naphthyl phenylglyoxylate proceeded to give the desired product in 86% yield and 94% ee. Moderate to good yields (65-95%) and good ee's (90-95%) were obtained with arylboronic acids with diverse steric and electronic properties. 
 
 
Figure 4 - Various reactions of N-sulfinyl imines
 
Addition to α-diketones (benzyl) under optimised conditions was then found to provide the desired product in 97% yield and 97% ee. Again, the steric and electronic properties of the boronic acid did not affect the outcome. The reaction is also effective for substituted dibenzyls and other diketones. In the case of unsymmetrical diketones, regio- and enantioselectivity was observed, with addition to the less hindered and less electron-deficient carbonyl group predominating.
 
The example of catalytic enantioselective addition with boronic acids to provide optically active tertiary α-hydroxyketones was unprecedented, according to Xu. In particular, the method was successfully applied to the synthesis of chiral 1,3-dihydroisobenzofurans, which are difficult to access by available asymmetric methods and are valuable pharmacological compounds.
 
Not surprisingly, the chiral N-(sulfinyl)cinnamylamine ligand is also effective in the rhodium-catalysed conjugate addition of phenyl boronic acids to cyclic enones, esters and amides. To demonstrate its practicality, the reaction was scaled up to 5 mmol with a cyclic amide using 1 mol% catalyst. A 75% yield with 95% ee was obtained. Modest yields (60%) and enantioselectivities (80%) were also achieved with acyclic substrates. 
 
In addition to these chiral sulfinyl-olefin hybrid ligands, Xu has developed several other asymmetric transformations using chiral N-tertbutanesulfinyl imines. The zinc-promoted benzyolyoxyallylation of chiral N-tertbutanesulfinyl imines with 3-bromopropenyl benzoate at room temperature proceeds with high diasteroselectivity (up to 99:1) in favor of the anti isomer and serves as a new route for the direct α-hydroxyallylation of imines with enantio-induction of two new stereogenic centres in up to 98% ee. Interestingly, the stereoselectivity is reversed if the solvent is changed from HMPA to THF.
 
The asymmetric synthesis of β-aryl substituted homoallylic amines bearing two adjacent stereogenic centres was also achieved through the zinc-mediated cinnamylation of N-sulfinyl imines. The same solvent affect on stereoselectivity was observed with this reaction, but it was also found that addition of LiCl to THF caused the reversal as well.
 
The SmI2 mediated cross-coupling of chiral N-tert-butylsulfinyl imines with aldehydes results in formation of enantiomerically pure β-amino alcohols with an anti orientation. This reaction was applied to the synthesis of (+)-febrifugine.
 
Chiral N-tert-butylsulfinylamino esters can also undergo Friedel-Crafts reaction with unprotected indoles to produce enantiomerically enriched α-(3-indoyl)glycines, which are found in many biologically natural and unnatural products. The N-tert-butanesulfinylimino ester of ethyl glyoxylate reacts with indoles in the presence of 10 mol% Cu(OTf)2 over 30 minutes to give 79% yield of the desired simple indole with 98% diastereoselectivity. 
 
A wide range of indoles bearing different substituents provided products with diastereoselectivities generally above 90%. A similar strategy was also found to be successful in the reactions of arenes with N-tert-butanesulfinylimino ester to provide chiral α-arylglycines. The sulfinyl group can be readily removed under mild acidic conditions with complete retention of the stereochemical configuration.
 
Optically active allenylglycines were also prepared via the indium-mediated allenylation of N-tert-butanesulfinyl imino esters. Reaction of tert-butanesulfinyl imino ethyl ester and propargylic bromides in water and THF (1:1) with NaI additive at room temperature for four hours gave the desired products in good yields and selectivities (95-99%). The products can be converted into highly enantiomerically pure proline derivatves in three steps.
 
Xu also developed a high yield, one-pot asymmetric synthesis of highly substituted γ-lactams containing α-methylene groups with diastereoselectivity for the trans isomer up to 99:1. The transformation involves the reaction of β,γ-disubstituted allyl bromides and chiral sulfinyl imines and generates two new stereogenic centres with an ee of 99%.

From Online Issue: February 2012