10-Camphorsulfonic Acid

(1S)-(+)

[3144-16-9]  · C10H16O4S  · 10-Camphorsulfonic Acid  · (MW 232.30) (1R)-(-)

[35963-20-3] (±)

[5872-08-2]

(acid catalyst,1-8 resolving agent,9,10 chiral auxiliary11-20)

Physical Data: mp 203-206 °C (dec).

Solubility: sol dichloromethane, methanol, benzene; insol ether.

Form Supplied in: white crystals, racemic (±).

Analysis of Reagent Purity: melting point, NMR.

Preparative Methods: commercially available from several sources; can be prepared by sulfonation of camphor with acetic-sulfuric anhydride.21

Purification: recrystallize from ethyl acetate.

Handling, Storage, and Precautions: hygroscopic; corrosive.

Acid Catalyst.

Camphorsulfonic acid (CSA) has been used extensively in synthetic organic chemistry as an acid catalyst. It has particularly been used in protecting group chemistry. For example, hydroxyl groups can also be protected as tetrahydropyranyl (THP) ethers using dihydropyran and a catalytic amount of CSA (eq 1).1 Both 1,2- and 1,3-diols can be selectively protected by reaction with orthoesters in the presence of camphorsulfonic acid to form the corresponding cyclic orthoester (eq 2).2 This method of protection is particularly useful in that reduction of the orthoester with Diisobutylaluminum Hydride forms the monoacetal, which allows for preferential protection of a secondary alcohol in the presence of a primary alcohol. Ketones have also been protected using catalytic CSA (eq 3).3

Overman has shown that camphorsulfonic acid can also be used in nucleophile-promoted alkyne-iminium cyclizations.22 Alkylamines can react with formaldehyde and sodium iodide to yield piperidines in good yield. This methodology has been applied in the total synthesis of pumiliotoxin A (eq 4).4

The most efficient catalyst for intramolecular opening of epoxides is CSA.5,6 The formation of tetrahydrofurans or tetrahydropyrans is highly dependent on the structure of the hydroxy epoxide. The presence of a saturated chain at the secondary epoxide position leads to formation of tetrahydrofurans (eq 5)5 via 5-exo ring closure, whereas an electron-rich double bond at this position gives tetrahydropyrans (eq 6)6 via 6-endo ring closure. This methodology has also been extended to the synthesis of oxepanes (eq 7).6

CSA is also the acid of choice for use in phenylselenation reactions.7 It has been used as an acid catalyst in hydroxyselenation reactions of alkenes (eq 8)7 and organoselenium-induced cyclizations (eq 9) using N-Phenylselenophthalimide (NPSP).7

CSA has also been used to catalyze spiroacetalizations.8,22 In Schreiber's approach to the talaromycins he utilized a CSA-catalyzed spiroacetalization (eq 10) and found that the use of different solvents led to varying percentages of isomeric products.8 Other approaches to the talaromycins also utilize CSA for the required spiroacetalization.23

Resolving Agent.

Scalemic CSA has been used to resolve amines by forming diastereomeric salts which can be separated by fractional crystallization (eq 11).9 In this instance, after obtaining the desired crystalline diastereomeric salt, the undesired diastereomer was completely transformed into the desired one by a resolution-racemization procedure (eq 12).9 Additionally, racemic ketones can be resolved by forming enantiomeric iminium salts (eq 13).10 Two different procedures have been devised depending on the ease of enamine formation.

Chiral Auxiliaries.

Asymmetric Diels-Alder Reactions.

The commercial availability of either enantiomer of camphorsulfonic acid has made it quite useful in asymmetric Diels-Alder reactions. Reaction of the sultone (generated from CSA) with Lithium Diisopropylamide followed by esterification and b-elimination yields the crystalline acrylate (eq 14).11 The Lewis acid-catalyzed [4 + 2] cycloaddition of 1,3-dienes with this acrylate affords the corresponding scalemic adduct which can be reduced with Lithium Aluminum Hydride to yield an enantiomerically pure alcohol (eq 15).12

A different approach to the asymmetric Diels-Alder reaction involves the use of the sultam derived from CSA. Lewis acid-promoted reaction with dienes followed by reductive removal of the chiral auxiliary is analogous to that previously discussed for the sultone. Smith has successfully utilized this approach to synthesize the chiral acid used in the synthesis of the immunosuppressant FK-506 (eq 16).13

Oxaziridines.

Davis has developed the use of chiral 2-sulfonyloxaziridines derived from camphorsulfonic acid as chiral auxiliaries in the asymmetric oxidation reactions.24 Although other oxaziridines may be preferable, the camphor-derived oxaziridines can be used for the oxidation of sulfides and disulfides to sulfoxides and thiosulfinates as well as for the epoxidation of alkenes.24 On the other hand, the camphoryloxaziridines are the preferred reagents for hydroxylation of lithium enolates of esters, amides, and ketones, as utilized in the synthesis of kjellmanianone (eq 17).14

Chiral Sulfides.

Optically active sulfides prepared from (+)-CSA can be used to prepare optically active 1,2-diaryloxiranes (eq 18).15

Grignard Addition to Enones.

The sultam generated from camphorsulfonic acid can also be used as a chiral auxiliary in the conjugate addition of Grignard reagents to enones. Simple alkylmagnesium chlorides add in a 1,4-fashion to afford imides (eq 19).16

Asymmetric Hydrogenation of Camphor-Derived Sultamides.

The sultamide of CSA can be used as a chiral auxiliary for synthesis of b-substituted carboxylic acids (eq 20).17

Asymmetric Acetoxylation of Esters.

The silyl enol ether derived from CSA reacts with Lead(IV) Acetate to yield the a-acetoxy ester with good diastereoselectivity. Hydrolysis of the chiral auxiliary gives the a-hydroxy acid, whereas reduction affords the terminal a-glycol (eq 21).18

Allylation of Aldehydes.

Synthesis of enantiomerically pure allyl alcohols can be accomplished by catalytic asymmetric addition of divinylzinc to aldehydes using a camphorsulfonic acid-derived catalyst (eq 22).19

Synthesis of Epoxides from Chiral Chlorohydrins.

Asymmetric halogenation of CSA-derived esters allows for the formation of enantiomerically pure halohydrins and terminal epoxides (eq 23).20


1. Nicolaou, K. C.; Chakraborty, T. K.; Daines, R. A.; Simpkins, N. S. CC 1986, 413.
2. Takasu, M.; Naruse, Y.; Yamamoto, H. TL 1988, 29, 1947.
3. Tamai, Y.; Hagiwara, H.; Uda, H. JCS(P1) 1986, 1311.
4. Overman, L. E.; Sharp, M. J. TL 1988, 29, 901.
5. Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. JACS 1989, 111, 5330.
6. Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. JACS 1989, 111, 5335.
7. Nicolaou, K. C.; Petasis, N. A.; Claremon, D. A. T 1985, 41, 4835.
8. Schreiber, S. L.; Sommer, T. J.; Satake, K. TL 1985, 26, 17.
9. Reider, P. J.; Davis, P.; Hughes, D. L.; Grabowski, E. J. J. JOC 1987, 52, 955.
10. Adams, W. R.; Chapman, O. L.; Sieja, J. B.; Welstead, W. J., Jr. JACS 1966, 88, 162.
11. Oppolzer, W.; Chapuis, C.; Kelly, M. J. HCA 1983, 66, 2358.
12. Oppolzer, W.; Chapuis, C.; Bernardinelli, G. TL 1984, 25, 5885.
13. Smith, A. B., III; Hale, K. J.; Laakso, L. M.; Chen, K.; Riéra, A. TL 1989, 30, 6963.
14. Boschelli, D.; Smith, A. B., III; Stringer, O. D.; Jenkins, R. H., Jr. Davis, F. A. TL 1981, 22, 4385.
15. Furukawa, N.; Sugihara, Y.; Fujihara, H. JOC 1989, 54, 4222.
16. Oppolzer, W.; Poli, G.; Kingma, A. J.; Starkemann, C.; Bernardinelli, G. HCA 1987, 70, 2201.
17. Oppolzer, W.; Mills, R. J.; Réglier, M. TL 1986, 27, 183.
18. Oppolzer, W.; Dudfield, P. HCA 1985, 68, 216.
19. Oppolzer, W.; Radinov, R. N. TL 1988, 29, 5645.
20. Oppolzer, W.; Dudfield, P. TL 1985, 26, 5037.
21. Bartlett, P. D.; Knox, L. H. OSC 1973, 5, 194.
22. Overman, L. E.; Sharp, M. J. JACS 1988, 110, 612.
23. Baker, R.; Boyes, A. L.; Swain, C. J. TL 1989, 30, 985.
24. Davis, F. A.; Jenkins, R. H., Jr.; Awad, S. B.; Stringer, O. D.; Watson, W. H.; Galloy, J. JACS 1982, 104, 5412.

Ellen M. Leahy

Affymax Research Institute, Palo Alto, CA, USA



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