In the Laboratory
Synthesis of Derivatives of (1R)-(–)- and (1S)-(+)-10-Camphorsulfonic Acid
W
Steven C. Cermak and David F. Wiemer* Department of Chemistry, University of Iowa, Iowa City, IA 52242; *
[email protected] Interest in chemical syntheses that afford products of defined absolute stereochemistry has grown substantially in recent years as, for example, the benefits of pharmaceutical agents that are single enantiomers rather than racemates have become recognized (1). At the same time, concepts such as enantiomeric excess (ee) and the lack of correlation between absolute configuration and optical rotation are difficult for many students to grasp when they are first introduced in organic chemistry lectures. Furthermore, there are limited numbers of experiments for organic laboratory courses that can be used to illustrate these concepts (2). These considerations led us to develop a new series of experiments for undergraduate organic laboratory to illustrate these concepts, based on preparation of camphorsulfonyloxaziridine derivatives. The use of camphorylsulfonyloxaziridine, a Davis reagent, for synthesis of chiral compounds is of current interest (3). The oxaziridines are known to be excellent hydroxylating agents and have been shown to be effective with ketones (4 ), esters (5), amides (6 ), phosphonates (7), and other activated methylene positions (8). Enantioselective syntheses of αhydroxy carbonyl compounds have been reported that are based on oxidations with enantiomerically pure oxaziridines. As one example (eq 1), treatment of the ketone 1 with strong base and a Davis reagent gives the α-hydroxy ketone 2 in good chemical yield (77%) and with excellent enantioselectivity (≥96% ee). The development of highly enantioselective methods for construction of α-hydroxy carbonyl compounds is of significant interest because such functionality is common to many biologically active natural products. Synthesis of the oxaziridine reagents provides an interesting example of preparation of optically active molecules and involves a series of reactions that is easily conducted in a teaching laboratory. O
O CH3
1. Base 2. Davis Reagent
O
O
OH CH3
Table 1. Class Averages for Preparation of Camphorsulfonic Acid Derivatives (1S)-(+)-Camphorsulfonyl Chloride Compound
[α]
(1R)-(–)-Camphorsulfonyl Chloride
yield (%)
Compound
[α]
ee a (%)
yield (%)
(+)- 4
+32.0
97
—
(–)- 4
{28.6
87
—
(–)- 6
{33.9
98
66
(+)- 6
+22.7
70
38
(+)- 7
+39.6
89
43
(–)- 7
{44.9
100
49
(+)- 8
+6.4
77
82
(–)- 8
—
—
—
NOTE: These results are the averages obtained by the undergraduate students in our laboratory sections that employed the conditions listed in the experimental section. aEnantiomeric excess (ee) = (% major enantiomer – % minor enantiomer) and is determined by comparison of the measured optical rotation with known values (5) for enantiomerically pure material. For compound (+)-4, 97% ee corresponds to 98.5% of the (+)-enantiomer and 1.5% of the (–)-enantiomer.
and intermediates can be taken in organic solvents such as CHCl3 and correspond well with literature values. The synthetic sequence from the sulfonic acid 3 to oxaziridine 7 demonstrates that optical rotation cannot be readily predicted and allows students to determine enantiomeric excess at each stage. Students are intrigued by the switch in rotation and see first-hand that even the direction of the optical rotation is not readily predicted. Finally, some students can be issued one enantiomer of the starting material while others are issued the opposite enantiomer. Allowing students to decide in a team atmosphere which of the final products should be combined to afford material for potential follow-up applications introduces a cooperative element to this experiment. Results from two classes that have used this experiment at the University of Iowa, totaling approximately 80 students over two years, are displayed in Table 1.
(1) -H2O
O SO2NH2
O SO2X
Summary of Procedures Synthesis of (+)- and (–)-((camphoryl)sulfonyl)oxaziridine (7), or the closely related reagents (+)- and (–)-8,8-((dichlorocamphoryl)sulfonyl)oxaziridine (9), which sometimes give higher enantioselectivity in oxidations, can be accomplished through the reaction sequence shown in Scheme I. Both enantiomers of camphorsulfonic acid and camphorsulfonyl chloride are commercially available. If the less expensive enantiomeric series (i.e., (1S)-(+)-camphorsulfonic acid, 3) is employed, the optical rotations are positive for the sulfonic acid 3, the acid chloride 4, and the amide 5, then negative for the imine 6, and finally positive for oxaziridine 7 and dichloroimine 8. The optical rotations of the final product
H3CCO3H
H+
NH4OH
2
1
ee a (%)
5
SO2
6
3 X = OH 4 X = Cl
N
N SO2
O
7 DCDMH
PCl3
Cl Cl
Cl [ox]
Cl N
N SO2
SO2 8
9
O
Scheme I
The entire sequence of experiments was conducted in four 3-hour laboratory periods and used to illustrate a synthetic sequence, cumulative yield, recrystallization, oxidation, and analysis of NMR spectra in addition to the central concept
JChemEd.chem.wisc.edu • Vol. 76 No. 12 December 1999 • Journal of Chemical Education
1715
In the Laboratory
of optical activity and enantiomeric excess. However, if less time were available, selected transformations could be used to focus on the issues of absolute configuration and optical rotation. For example, conversion of compound 6 to oxaziridine 7 can be done in one lab period and illustrates one inversion of the optical rotation while retaining absolute stereochemistry. In our course, pairs of students were asked to conduct a three-step reaction sequence from the sulfonyl chloride 4 to either compound 7 or 8. Each pair conducted the synthesis, established yield, and estimated purity by determining melting points and optical rotations of the products. All pairs completed preparation of compound 6, but then half of each section was asked to prepare the oxaziridine 7 and half was asked to prepare the dichloro compound 8 (which can be oxidized to oxaziridine 9 by a procedure analogous to that used for preparation of oxaziridine 7, if desired). Each section was asked to determine which samples should be combined to afford material for subsequent experiments, and pooled yields, chemical purity, and optical purity were compared between the two sections. The students should discuss the logic involved in determining which samples should be combined, considering total pooled yield, chemical purity, and optical purity. Students readily recognize that some have begun with one enantiomer and others with its mirror image, once they obtain optical rotations. As part of their spectral analysis, the students were given a 1H NMR FID of intermediate 6, because that compound was the last common intermediate. They were asked to process the FID using the program NUTS (Acorn Software) to obtain a frequency domain spectrum, and then to interpret the transformed spectrum. The 1H NMR spectrum of compound 6 displays a classic example of diastereotopic hydrogens on the –CH2– group α to sulfur. The acid chloride 4 is sensitive to hydrolysis, and if it cannot be converted to the sulfonamide 5 immediately after its formation, significant decomposition may be observed. Thus if lab time is limited it may be advantageous to begin this sequence with commercial acid chloride rather than the sulfonic acid. In contrast to the acid chloride, the subsequent compounds, including the imines 6 and 8 and the oxaziridine 7, are reasonably stable and readily crystallized. Each of the latter three compounds affords clean white crystals. While the initial reaction products may be of sufficient purity for use in the subsequent reaction, we have required students to crystallize each intermediate. Even though this results in somewhat decreased yields, as reflected in Table 1, students gain experience by conducting crystallizations in successive laboratory sessions.
1716
This sequence of experiments should be suitable for students in a college-level course in organic chemistry, after concepts of stereochemistry have been introduced in an organic lecture course. Depending on the available time, students can conduct the entire sequence, or commercial intermediates can be purchased (Aldrich) to allow students to focus on the later reactions where the changes in optical rotation are most pronounced. Demonstration of this point requires access to a polarimeter, but otherwise only standard laboratory equipment is required. Acknowledgments We thank our teaching assistants (Liqiang Chen, Kevin E. Helwig, Sarah A. Holstein, and Edward M. Treadwell) for their efforts in testing these experimental procedures prior to their use in laboratory sections. Note W
Supplementary materials for this article are available on JCE Online at http://jchemed.chem.wisc.edu/Journal/issues/1999/Dec/ abs1715.html.
Literature Cited 1. Thall, E. J. Chem. Educ. 1996, 73, 481–484. For one example of the different activity of two enantiomers, see Lampe, J. W.; Hughes, P. F.; Biggers, C. K.; Smith, S. H.; Hu, H. J. Org. Chem. 1996, 61, 4572–4581. 2. Two experiments have been used to illustrate these concepts in our laboratory, one involving preparation of the (S)-(+)-Wieland– Meischer ketone and the other based on preparation of (R)-(+)3-methyladipic acid. See Markgraf, J. H.; Fei, J. F.; Ruckmen, R. E. J. Chem. Educ. 1995, 72, 270–271. Scott, W. J.; Hammond, G. B.; Becicka, B. T.; Wiemer, D. F. J. Chem. Educ. 1993, 70, 951–952. 3. Davis, F. A.; Kumar. A.; Chen, B. C. J. Org. Chem. 1991, 56, 1143. Davis, F. A.; Sheppard, A. C.; Chen, B. C.; Serajul Haque, M. J. Am. Chem. Soc. 1990, 112, 6679. 4. Davis, F. A.; Weismiller, M. C. J. Org. Chem. 1990, 55, 3715. Davis, F. A.; Weismiller, M. C.; Murphy, C. K.; Thimma Reddy, R.; Chen, B. C. J. Org. Chem. 1992, 57, 7274–7285. 5. Davis, F. A.; Serajul Haque, M.; Ulatowski, T. G.; Towson, J. C. J. Org. Chem. 1986, 51, 2402–2404. 6. Davis, F. A.; Ulatowski, T. G.; Serajul Haque, M. J. Org. Chem. 1987, 21, 5288–5290. 7. Pogatchnik, D.; Wiemer, D. F. Tetrahedron Lett. 1997, 38, 3495–3498. Cermak, D. M.; Du, Y.; Wiemer, D. F. Org. Chem. 1999, 64, 388–393. 8. Eguchi, S.; Suzuki, T.; Okawa, T.; Matsushita, Y. J. Org. Chem. 1996, 61, 7316–7319.
Journal of Chemical Education • Vol. 76 No. 12 December 1999 • JChemEd.chem.wisc.edu
