1. Chiral Sulfoxides: A Whirlwind Tour Literature Presentation Scott Jarvis April 27 th, 2010

2. Characteristics of Sulfoxides Sulfoxides have high optical stability, in general the racemization of sulfoxides only occurs at an appreciable rate at 200 o C except Benzyl and allyl sulfoxides whose racemization occurs at lower temperatures, 130- 150 o C and 50-70 o C respectively. Sulfoxides are accessible in both enantiomeric forms The large stereoelectronic differences between the three types of substituents (oxygen, electron lone pair, and two alkyl or aryl groups) at the sulfinyl sulfur allow the creation of a well defined chiral environment around the sulfur atom, therefore they are efficient as carriers of chiral information

3. Methods to Prepare Chiral Sulfoxides Oxidative methods ◦ Diastereoselective ◦ Modified sharpless oxidation ◦ Salen oxidation ◦ Chiral oxaziridines ◦ Chiral epoxides Nucleophilic substitution methods ◦ Andersen Methodology (menthol) ◦ Aminosulfites (ephedrine, aminoindane) ◦ Sulfites (lactate derivative, sugars) ◦ Evans auxillary ◦ Oppolzer’s Sulfinylsultam Combination ◦ Thiosulfinate approach(tert-Butyl-SO-R)

4. Diastereoselective Oxidation The oxidation of sulfur can be directed by a coordinating atom such as N or O or straight steric bulk Synthesis, 1992, 555 Tet. Lett., 1993, 7877

5. Diastereoselective Oxidation Chem. Comm., 1998. 2763

6. Modified Sharpless Oxidation Mostly relies on steric bulk to gain the selectivity R1R1 R2R2 Yield (%)ee (%) ( R ) PhenylMe8191.2 p-TolylMe7795.6 p-anisylMe7392.1 o-anisylMe7289.3 o-nitrophenylMe5175.0 PhenylCH=CH 2 5855.4 p-TolylEt6878.1 p-Tolyln-butyl7025.0 o-anisylphenyl646.2 benzylMe7290.3 n-octylMe6970.7 Bull. Soc. Chim. Fr., 1996, 1109 Synlett, 1996, 404 (Kagan)

7. Modified Sharpless Oxidation Other diols have been used in place of DET

8. Uemura’s Binol Version ArSolventMethodYield (%) ee (%) ( R ) p-tolylCCl 4 A6584 p-tolylCCl 4 B6793 p-tolylCCl 4 B a 6488 p-tolylCCl 4 C4496 p-tolylCHCl 3 A7423 p-tolylDCMA8416 p-tolylDCEA8625 p-tolylTolueneA6672 p-tolylo-xyleneA8861 p-tolylcumeneA8657 p-tolylTHFA4672 p-tolylDiethyl etherA3257 PhCCl 4 A8065 PhTolueneA8663 2-NapthylCCl 4 A7351 p-BrC 6 H 4 CCl 4 A6268 n-octylCCl 4 B6469 Method A: under Ar peroxide in toluene Method B: under Air, peroxide in water Method C: Half as much catalyst Note a: under Argon JOC, 1993, 4529

9. Modified Sharpless Oxidation H-Bonding under specific conditions can also give good selectivity (but very sensitive). Tet. Asymm., 2000, 3819

10. Salen Oxidation Typically thought of for chiral epoxidation of olefins but with modifications they are useful for sulfide oxidations. JACS, 2007, 8940. Catalyst Yield (sulfoxide) Yield (sulfone) ee of sulfoxide (%) R1R1 R2R2 Yield (sulfoxide) Yield (Sulfone) ee of sulfoxide (S) (%) none40 p-MePhMe91996 130210 ( R )p-MeOPhMe92895 225210 ( S )p-ClPhMe762494 389588 ( S )o-ClPhMe97<196 492896 ( S )o-MeOPhMe99<195 PhEt782281 1 (R, R): R = HPhCH 2 Me93787 2 (R, R): R = Men-C 8 H 17 Me821889 3 (R, S): R = Hn-C 12 H 25 Me821894 4 (R, S): R = Mec-C 6 H 11 Me91988

11. Other Metal Catalyzed Oxidations RR'Yieldee (%) PhMe9470 PhiPr6462 PhN-C 10 H 21 7753 p-NO 2 PhMe5563 t-BuBn9165 ACIE, 1995, 2640 Synlett, 1998, 1327 RR'Yield ee (%) (cis) PhH8485 p-TolylH7977 p-Cl-PhH8764 p-MeO-PhH6057 o-Br-PhH8164 o-NO 2 -PhH7562 t-BuH6746 PhMe 44 (cis)68 37 (trans) 12 (trans)

12. Chiral Oxaziridine Oxidations Tet., 1988, 5703 JACS, 1989, 5964 JACS, 1988, 8477 JOC, 1992, 7274 Tet. Asymm., 1992, 629. Large RYield (%)ee (%) p-TolylH95>95 p-TolylPh7488 2-NapthylH8494 t-ButylH8494 t-ButylPh8094 n-octylH6045 ($50/g)

13. Top view Looking down the pocket between Ph and camphor

14. Top view

15. Chiral Peroxides Tet., 1997, 185 JOC, 1998, 3423

16. Summary of Oxidative Methods In general the oxidative methods require a large steric difference between the two sulfide substituents (ie: Ph vs Me) H-bonding can give selectivity despite a lack of large steric differences in some cases, though conditions are sensitive and difficult to optimize The oxaziridine oxidation works if the ‘small’ substituent is a methylene (or equally small such as vinyl) and the ‘large’ is phenyl or tert-butyl If the molecule is already chiral, diastereoselective oxidation can occur which depending on which isomer is desired could be an aid or a detriment

17. Andersen’s Nucleophilic Method Oldest method, other secondary carbinols have been used also Limited to Di-aryl or aryl/alkyl sulfoxides. For the synthesis of dialkyl sulfoxides, the required menthyl alkanesulfinate esters cannot be prepared enantiomerically pure at sulfur (they cannot be crystallized, since they’re oils). Tet. Lett., 1962, 93 JACS, 1992, 5977 JOC, 1984, 4070

18. Aminosulfite Pioneered by Wudl and Lee using ephedrine as a chiral auxillary (1973), modified by Snyder and Benson (AlMe 3, prevents racemisation). JACS, 1973, 6349 Tet. Lett., 1991, 5885

19. Kagan’s Sulfite Suitable for dialkyl, alkyl aryl, and diaryl sulfoxides giving enantiopure sulfoxides however tedious purifications (auxiliary derived from lactate). JOC, 1991, 5991 (Kagan)

20. Evan’s Auxiliary It was found that EWG’s on the N facilitate N-S cleavage, so Evan’s auxiliary was a logical step. Nucleophilic displacement occurs with inversion of configuration at the sulfur, and N-Sulfinyloxazolidinones are at least 2 orders of magnitude more reactive than Anderson’s menthyl sulfinate. JACS, 1992, 5977

21. Evan’s Auxiliary R1R1 R2R2 Yield (%) ee (%) p-TolMe9099 p-TolEt9098 p-Toli-Pr9197 p-Tolt-Bu8897 p-TolBn8699 PhMe8790 t-BuMe7893 BnMe8291 n-octylMe78100 Met-Bu92100 n-But-Bu91100 JACS, 1992, 5977

22. Oppolzer’s Sulfinylsultam Yields: 83-97%, ee’s 96 to >99% but only p-tolyl used for sulfinylsultam R The Sultam can be recovered and reused (recovered yields >90%) Tet. Lett., 1997, 2825.

23. Combination Approach to Chiral Sulfoxides R R1R1 Yield (%)ee (%) Men-octyl54>98% Men-decyl46>98% Men-octadecyl49>98% Mecyclohexyl509 Met-Bu15>98% Me(E)-2-styril43>98% Etn-octyl40 Etp-tolyl3691 Phmethyl6094 Php-tolyl4294

24. Summary of Nucleophilic Methods All nucleophilic methods use chiral auxiliaries that are available enantiopure and cheap. Diaryl sulfoxides can be made using: Anderson method, Kagan’s sulfite method, or Oppolzer’s method Aryl/alkyl sulfoxides can be made using any of the methods Di-alkyl sulfoxides or alkyl aryl sulfoxides can be made enantiopure using Evan’s auxillary, Snyder/Lee’s method, the ephedrine method or Kagan’s sulfite Of all the methods, Kagan’s method is the most versatile but least used since it is so tedious for the crystallizations. Evan’s auxiliary method is easy, and versatile giving aryl/alkyl and alkyl/alkyl sulfoxides.

25. Uses of sulfoxides Drug candidates/Natural product synthesis Ligands in Catalysis ◦ Hydrogenation ◦ Cyclo-additions (DA) ◦ C-C bond formation (Enone addition) Chiral Auxillaries (Main use) Chiral reagents ◦ NADH analog

26. Sulfoxides in Drugs Sulfoxides have a reputation for being potentially metabolically unstable - and they can go either way, being oxidized up to sulfones or reduced back to the parent sulfide. Sulfoxides have a strange character for drugs, because that oxygen atom is about as close to a naked O-minus as you're going to find in physiological conditions. The tetrahedral geometry of the sulfur means that this electronegative group is held is a very specific orientation relative to the other parts of your molecule (usually positive for binding to a target). Also, of course they're chiral. That can either be a bug or a feature, depending on your project and on your view of the world

27. Examples of Drugs and Natural Products

28. Sulfoxides as Ligands for Metals Generally metals bind through the oxygen of the sulfoxide, however the soft metals of the Pt group (Ru, Rh, Os, Ir) can also bind through the sulfur depending on the other ligands of the metal. According to the model of Davies sulfoxide coordination through O induces a decrease in the S=O bond order while the opposite occurs for coordination through S. Therefore, the bond length of the S-O lengthens for oxygen coordinated complexes and decreases for sulfur coordinated complexes. The difference in bond length can be observed by IR (thus one can determine the mode of bonding), with the typical IR frequencies for SO being 1080-1150 for DMSO-S and 890-95- for DMSO-O. The binding mode also affects the 1 H NMR, with coordination through O induces small downfield shifts (max 0.5ppm) and coordination through S induces larger downfield shifts (0.5-1.1ppm). Chem. Rev., 2004, 4203

29. Catalytic Hydrogenation First work was by James and coworkers in 1976 using (+)-methyl p-tolyl sulfoxide with disappointing results. Followed up by McMillan in 1977 using a diastereomic mixture of sulfoxides which gave low ee’s. J. Mol. Catal., 1976, 439 Can. J. Chem., 1977, 3927

30. Catalytic Hydrogenation JOC, 2000, 3010 Temp ( o C) Conversion (%) ee (%) 609965 403867 205780

31. JOC, 2000, 3010

32. Chiral Lewis Acid Catalyst for Diels-Alder Though not sulfoxides, the bis(sulfinyl)imidoamidine shown below gave moderate to excellent diastereoselectivity and enantioselectivity. JACS, 2001, 1539

33. Chiral Lewis Acid for Hetero-D.A. JACS, 2001, 3830

34. Diethylzinc Addition to Benzaldehyde Tet. Asymm., 1993, 727 JOC, 2002, 1346

35. Enone Addition JACS, 2010, 4552 JACS, 2008, 2172 ACIE, 2009, 2768

36. JACS, 2010, 4552

37. Sulfoxides as Chiral Auxilliaries “The reduction of beta-ketosulfoxides has been the most extensively investigated and used reaction involving the asymmetric induction of chiral sulfoxides.” Either stereoisomer can be obtained from the same beta-ketosulfoxide depending on the presence or absence of a lewis acid (ie: ZnCl 2 ). Sulfoxides are cleaved under ‘mild conditions’. Tetrahedron, 2006, 5559 Synth. Commun., 2000, 4467.

38. Perkin Trans. 1, 2000, 3143 Tet., 2001, 8469 There are few examples of gamma-ketosulfoxides being reduced selectively

39. Unconjugated Addition Reactions Sulfoxides have the ability to stabilize a negative charge on an adjacent carbon Deprotonation of the alpha carbon of the sulfoxide requires a strong base (ie: LiNH 2, LDA, n-BuLi, LiHMDS, etc.) High stereoselectivity usually requires steric hindrance in the vicinity of the alpha carbon and the use of an electrophile with a bulky group. If optically active sulfoxides give a poor diastereoselectivity the presence of another function such as an ester, sulfide or amide which can have a chelating effect in the transition state can improve the selectivity. JOC, 2000, 469

40. Tet, 2006, 5559

41. A combination of the chemistry of oxidation and alkylation can be useful for synthesis, such as that shown below which was used for a drug candidate program. Chem. Rev., 2003, 3651

42. Conjugated Addition (Michael Addition) Tet, 2007, 5559 JOC, 2000, 1758 OL, 2001, 29 RElectrophileYield (%)de (%) HMeI21>96 MeMeI59>96 PhMeI75>96 PhBnBr74>96 Phi-PrCHO90>96 PhPhCHO98>96

43. Conjugate Addition to Vinyl Sulfoxides Vinyl sulfoxides can act as Michael acceptors for a variety of nucleophiles (cuprates, enolates, malonates, amines, thiols, etc.) and due to the chirality can induce chirality at the beta-carbon, but at least creates diastereomers which can be separated with standard techniques. Tet. Asymm., 2005, 665 Tet. Lett., 2002, 3061

44. Sulfoxides as Chiral Auxillaries for D.A. “The sulfinyl group as, equally, become one of the most interesting chiral inductors in asymmetrics Diels-Alder reactions, due to: (a) its ability to differentiate between diastereotopics faces of neighboring double bonds, (b) the ease of chemical transformations in to different functional groups including its clean removal under mild conditions and (c) the existence of several efficient methods that allow the preparation of enantiomerically pure sulfoxides.” The substituents and lewis acid used to catalyze the reaction have a strong influence on which product is formed. Tet., 2006, 5559

45. Chem. Eur. J., 2000, 288

46. Chiral Reagents (NADH analog) A chiral NADH polymer supported reagent was prepared and shown to enantioselectively reduce the activated carbonyl shown below to an alcohol, and this reagent could be recycled using 1-propyl-1,4,- dihydronicotinamide. Heterocycles, 1998, 261

47. Pummerer Reaction (can be used for cleavage of a sulfoxide) Sulfoxides with an alpha Hydrogen when reacted with an activating group (ie: Ac 2 O, TFAA, TMSOTf, etc.) rearrange to give alpha substituted sulfides. This reaction allows the conversion of a sulfoxide to a carbonyl, or can transfer the sulfoxide chirality to the alpha carbon creating a chiral sulfide. Strategic Applications of Named Reactions in Organic Synthesis, 2005, L. Kurti and B. Czako

49. Some good reviews if interested ◦ Chem. Rev., 2010, ASAP (synthesis of sulfoxides) ◦ Chem. Rev., 2003, 3651 (synthesis of sulfoxides) ◦ Chem. Rev., 2004, 4203 (SO bonding to Pt metals) ◦ Tetrahedron, 2006, 5779 (as chiral auxilliaries) ◦ Chem. Rev., 2007, 5133 (asymmetric catalysis)