(Camphorylsulfonyl)oxaziridine1

(+)-(1)

[104322-63-6]  · C10H15NO3S  · (Camphorylsulfonyl)oxaziridine  · (MW 229.30) (-)-(1)

[104372-31-8]

(neutral, aprotic, electrophilic, and asymmetric oxidizing agents for the chemoselective oxidation of many nucleophilic substrates such as sulfides, enamines, enol esters, carbanions, and enolates1)

Physical Data: (+)-(1): mp 165-167 °C, [a]D +44.6° (CHCl3, c 2.2); (-)-(1): mp 166-167 °C, [a]D -43.6° (CHCl3, c 2.2).

Solubility: sol THF, CH2Cl2, CHCl3; slightly sol isopropanol, ethanol; insol hexane, pentane, water.

Form Supplied in: commercially available as a white solid.

Analysis of Reagent Purity: by mp and specific rotation determination.

Preparative Methods: the enantiopure (+)- and (-)-(camphorylsulfonyl)oxaziridines (1) and [(8,8-dichlorocamphor)sulfonyl]oxaziridines (2) are commercially available. They can also be prepared on a large scale via the oxidation of corresponding camphorsulfonimines with buffered Potassium Monoperoxysulfate (Oxone)2 or buffered peracetic acid.3 Since oxidation takes place from the endo face of the C=N double bond, only a single oxaziridine isomer is obtained. The precursor camphorsulfonimines can be prepared in 3 steps (>80% yield) from inexpensive (+)- and (-)-10-Camphorsulfonic Acids. A variety of (camphorylsulfonyl)oxaziridine derivatives such as (2)-(4) are also readily available via the functionalization of the camphorsulfonimines followed by oxidation.1,2-6

Purification: by recrystallization.

Handling, Storage, and Precautions: indefinitely stable to storage at room temperature and to exposure to air.

Asymmetric Oxidation of Sulfides.

Prochiral sulfides are oxidized by (camphorylsulfonyl)oxaziridine (1) to optically active sulfoxides. Over-oxidation to sulfones is not observed (eq 1).7 However, the best chiral N-sulfonyloxaziridines for the asymmetric oxidation of sulfides to sulfoxides are the (+)- and (-)-N-(Phenylsulfonyl)(3,3-dichlorocamphoryl)oxaziridines.8

Oxidation of Enamines.

Enamines are rapidly oxidized by (+)-(camphorylsulfonyl)oxaziridine (1). Disubstituted enamines give rise to racemic a-amino ketones, while trisubstituted enamines afford, after hydrolysis, a-hydroxy ketones (eq 2).9 A mechanism involving initial oxidation of the enamine to an a-amino epoxide is suggested to account for these products.

Oxidation of Oxaphospholenes.

Reaction of oxaphospholene (5) with (+)-[(8,8-dichlorocamphoryl)sulfonyl]oxaziridine (2) affords b-hydroxy-g-keto-phosphonate in 49% ee with undetermined absolute configuration (eq 3).10 Higher temperatures accelerate the reaction but lower the stereoselectivity.

Oxidation of Organolithium and Organomagnesium Compounds.

Oxidation of phenylmagnesium bromide and phenyllithium with (±)-trans-2-(Phenylsulfonyl)-3-phenyloxaziridine or (camphorylsulfonyl)oxaziridine (1) gives phenol (eq 4).11 Products are cleaner with the latter reagent because addition of the organometallic reagent to the C=N double bond of the imine is not observed. Oxidation of (E)- and (Z)-vinyllithium reagents with (+)-(1) affords enolates. The reaction is fast and represents useful methodology for the stereo- and regioselective formation of enolates.12 While the enolates can be trapped with Chlorotrimethylsilane to give silyl enol ethers, better yields and higher stereoselectivity are obtained with Bis(trimethylsilyl) Peroxide (eq 5).12

Oxidation of Phosphoranes.

Monosubstituted phosphoranes (ylides) are rapidly oxidized to trans-alkenes by (+)-(1), while disubstituted phosphoranes give ketones (eq 6). A mechanism involving initial attack of the carbanion of phosphorane to the electrophilic oxaziridine oxygen atom of (+)-(1) is proposed.13

Asymmetric a-Hydroxylation of Enolates.

a-Hydroxylation of enolates represents one of the simplest and most direct methods for the synthesis of a-hydroxy carbonyl compounds, a key structural unit found in many natural products.1b Enolate oxidations using (+)- and (-)-(1) and their derivatives generally effect this transformation in good to excellent yields with a minimum of side reactions (e.g. over-oxidation). Furthermore, these reagents are the only aprotic oxidants developed to date for the direct asymmetric hydroxylation of prochiral enolates to optically active a-hydroxy carbonyl compounds.

By choice of the appropriate reaction conditions and (camphorylsulfonyl)oxaziridine derivative, acyclic a-hydroxy ketones of high enantiomeric purity have been prepared.1 An example is the oxidation of the sodium enolate of deoxybenzoin with (+)-(1). The reaction proceeds very fast at -78 °C, affording (+)-(S)-benzoin in 95% ee. Both benzoin enantiomers are readily available by choice of (+)- or (-)-(1), because the configuration of the oxaziridine controls the absolute stereochemistry of the product (eq 7).14 Detailed studies have indicated that the generation of a single enolate regioisomer is a pre-condition for high enantioselectivity, although this does not necessarily always translate into high ee's. Hydroxylation of tertiary substituted acyclic ketone enolates usually gives lower stereoselectivities due to the formation of (E/Z) enolate mixtures (eq 8).14 In addition to enolate geometry, the molecular recognition depends on the structure of the oxidant, the type of enolate, and the reaction conditions.1b Generally the stereoselectivity can be predicted by assuming that the oxaziridine approaches the enolate from the least sterically hindered direction.

The asymmetric hydroxylation of cyclic ketone enolates, particularly the tetralone and 4-chromanone systems, has been studied in detail because the corresponding a-hydroxy carbonyl compounds are found in many natural products.1b Some general trends have been observed. 2-Substituted 1-tetralones having a variety of groups at C-2 (Me, Et, Bn) are best oxidized by chlorooxaziridine (2) in >90% ee (eq 9).2c,15,16 However, substitution of a methoxy group into the 8-position lowers the stereoselectivity. For the 8-methoxytetralones, (8,8-dimethoxycamphorylsulfonyl)oxaziridine (3) is the reagent of choice. Similar trends have also been observed in 4-chromanones.1b Oxidation of the lithium enolate of (6) with (8,8-methoxycamphorsulfonyl)oxaziridine (3) affords 5,7-dimethyleucomol (7) in &egt;96% ee (eq 10).17 Hydroxylation of the enolate of 1-methyl-2-tetralone (8) to (9) gives poor to moderate stereoselectivities. The optimum result, 76% ee, is obtained using the sodium enolate and oxaziridine (+)-(1) (eq 11).15

It should be pointed out that enolates are oxidized by the (camphorylsulfonyl)oxaziridine at a much faster rate than sulfides. An example is the preparation of a-hydroxy ketone sulfide (9), an intermediate for the total synthesis of (±)-breynolide (eq 12).18

The asymmetric hydroxylation of ester enolates with N-sulfonyloxaziridines has been less fully studied.1b Stereoselectivities are generally modest and less is known about the factors influencing the molecular recognition. For example, (R)-methyl 2-hydroxy-3-phenylpropionate (10) is prepared in 85.5% ee by oxidizing the lithium enolate of methyl 3-phenylpropionate with (+)-(1) in the presence of HMPA (eq 13).19 Like esters, the hydroxylation of prochiral amide enolates with N-sulfonyloxaziridines affords the corresponding enantiomerically enriched a-hydroxy amides. Thus treatment of amide (11) with LDA followed by addition of (+)-(1) produces a-hydroxy amide (12) in 60% ee (eq 14).19 Improved stereoselectivities were achieved using double stereodifferentiation, e.g. the asymmetric oxidation of a chiral enolate. For example, oxidation of the lithium enolate of (13) with (-)-(1) (the matched pair) affords the a-hydroxy amide in 88-91% de (eq 15).20 (+)-(Camphorsulfonyl)oxaziridine (1) mediated hydroxylation of the enolate dianion of (R)-(14) at -100 to -78 °C in the presence of 1.6 equiv of LiCl gave an 86:14 mixture of syn/anti-(15) (eq 16).21 The syn product is an intermediate for the C-13 side chain of taxol.

Hydroxylation of the sodium enolate of lactone (16) with (+)-(1) gives a-hydroxy lactone in 77% ee (eq 17).15 Kinetic resolution and asymmetric hydroxylation with (camphorsulfonyl)oxaziridines has been applied to the synthesis of enantiomerically enriched a-hydroxy carbonyl compounds having multiple stereocenters, which may otherwise be difficult to prepare.22 Thus hydroxylation of the enolate of racemic 3-methylvalerolactone with substoichiometric amounts of (-)-(1) affords (2S,3R)-verrucarinolactone in 60% ee (eq 18) which on recrystallization is obtained enantiomerically pure.22

Oxidation of the dienolate of (17) with (+)-(1) affords a-hydroxy ester (18), a key intermediate in the enantioselective synthesis of the antibiotic echinosporin (eq 19),23 whereas oxidation of enolates derived from 1,3-dioxin vinylogous ester (19) gives rise to both a- and g-hydroxylation depending on the reaction conditions (eq 20).24 With (+)-(1) the lithium enolate of (19) gives primarily the a-hydroxylation product (20), while the sodium enolate gives g-hydroxylation product (21). Only low levels of asymmetric induction (ca. 16% ee) are found in these oxidations. Birch reduction products are also asymmetrically hydroxylated in situ by (+)-(1) (eq 21).25

Few reagents are available for the hydroxylation of stabilized enolates such as b-keto esters, e.g. Vedejs' MoOPH reagent (Oxodiperoxymolybdenum(pyridine)(hexamethylphosphoric triamide)) fails.26 On the other hand, oxaziridines hydroxylate such enolates in good yield with good to excellent stereoselectivities.1b For example, enantioselective hydroxylation of the potassium enolate of the b-keto ester (22) with methoxyoxaziridine (-)-(3) affords (R)-(+)-2-acetyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthol (23), a key intermediate in the asymmetric synthesis of the anthracycline antitumor agents demethoxyadriamycin and 4-demethoxydaunomycin (eq 22).27 Hydroxylation of the sodium enolate of enone ester (24) furnishes kjellmanianone (25), an antibacterial agent isolated from marine algae (eq 23).5 With (+)-(1) the ee's are modest (ca 40%), but improved to 69% ee with benzyloxaziridine (4).


1. (a) Davis, F. A.; Sheppard, A. C. T 1989, 45, 5703. (b) Davis, F. A.; Chen, B.-C. CRV 1992, 92, 919.
2. (a) Towson, J. C.; Weismiller, M. C.; Lal, G. S.; Sheppard, A. C.; Davis, F. A. OS 1990, 69, 158. (b) Towson, J. C.; Weismiller, M. C.; Lal, G. S.; Sheppard, A. C.; Kumar, A.; Davis, F. A. OS 1993, 72, 104. (c) Davis, F. A. Weismiller, M. C.; Murphy, C. K.; Thimma Reddy, R.; Chen, B.-C. JOC 1992, 57, 7274.
3. Mergelsberg, I.; Gala, D.; Scherer, D.; DiBenedetto, D.; Tanner TL 1992, 33, 161.
4. Davis, F. A.; Kumar, A.; Chen, B.-C. JOC 1991, 56, 1143.
5. Chen, B.-C.; Weismiller, M. C.; Davis, F. A.; Boschelli, D.; Empfield, J. R.; Smith, III, A. B. T 1991, 47, 173.
6. (a) Glahsl, G.; Herrmann, R. JCS(P1) 1988, 1753. (b) Meladinis, V.; Herrmann, R.; Steigelmann, O.; Muller, G. ZN(B). 1989, 44b, 1453.
7. Davis, F. A.; Towson, J. C.; Weismiller, M. C.; Lal, G. S.; Carroll, P. J. JACS. 1988, 110, 8477.
8. (a) Davis, F. A.; Thimma Reddy, R.; Weismiller, M. C. JACS, 1989, 111, 5964. (b) Davis, F. A.; Thimma Reddy, R.; Han, W.; Carroll, P. J. JACS 1992, 113, 1428.
9. Davis, F.; Sheppard, A. C. TL 1988, 29, 4365.
10. McClure, C. K.; Grote, C. W. TL 1991, 32, 5313.
11. Davis, F. A.; Wei, J.; Sheppard, A. C.; Gubernick, S. TL 1987, 28, 5115.
12. Davis, F. A.; Lal, G. S.; Wei, J. TL 1988, 29, 4269.
13. Davis, F. A.; Chen, B.-C. JOC 1990, 55, 360.
14. Davis, F. A.; Sheppard, A. C.; Chen., B.-C.; Haque, M. S. JACS 1990, 112, 6679.
15. Davis, F. A.; Weismiller, M. C. JOC 1990, 55, 3715.
16. Davis, F. A.; Kumar, A. TL 1991, 32, 7671.
17. Davis, F. A.; Chen, B.-C. TL 1990, 31, 6823.
18. Smith, III, A. B.; Empfield, J. R.; Rivero, R. A.; Vaccaro, H. A. JACS 1991, 113, 4037.
19. Davis, F. A; Haque, M. S.; Ulatowski, T. G.; Towson, J. C. JOC 1986, 51, 2402.
20. Davis, F. A.; Ulatowski, T. G.; Haque, M. S. JOC 1987, 52, 5288.
21. Davis, F. A.; Thimma Reddy, R.; Reddy, R. E. JOC 1992, 57, 6387.
22. Davis, F. A.; Kumar, A. JOC, 1992, 57, 3337.
23. Smith, III, A. B.; Sulikowski, G. A.; Fujimoto, K. JACS 1989, 111, 8039.
24. Smith III, A. B.; Dorsey, B. D.; Ohba, M.; Lupo Jr., A. T.; Malamas, M. S. JOC 1988, 53, 4314.
25. Schultz, A. G.; Harrington, R. E.; Holoboski, M. A. JOC 1992, 57, 2973.
26. (a) Vedejs, E.; Larsen, S. OS 1985, 64, 127. (b) Vedejs, E.; Engler, D. A.; Telschow, J. E. JOC 1978, 43, 188. Vedejs, E. JACS 1974, 96, 5944.
27. Davis, F. A.; Kumar, A.; Chen, B.-C. TL 1991, 32, 867. Davis, F. A.; Clark, C.; Kumar, A., Chen, B.-C. JOC 1994, 59, 1184.

Bang-Chi Chen

Bristol-Myers Squibb Company, Syracuse, NY, USA

Franklin A. Davis

Drexel University, Philadelphia, PA, USA



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