Application of NMR Techniques to the Structural Determination of Caryophyllene Oxide (Unknown #92)

Transcription

1 Application of NMR Technique to the Structural Determination of Caryophyllene xide (Unknown #92) C22 (Photo courtey of Dr. Kazuo Yamaaki, irohima Univerity) Chritopher J. Morten & Brian A. Sparling 5.4 Spring 2007

2 3 C 3 C S R Z S R C R E 13 C S R 9 7 S S R 5 Figure 1. Structure of (-)-caryophyllene oxide, or (1R,4R,R,S)-4,12,12-trimethyl-9- methylene-5-oxatricyclo[.2.0.0]4,)]dodecane. Carbon C1 C2 C3 C4 C C7 C C9 C C11 C12 C13 C C15 C1 Shift (ppm) C Integration m w m w w Table 1. Carbon ignal of caryophyllene oxide.

3 Proton Shift (ppm) & Int. Expected Mult. berved Mult. J Value (z) Environment** (1) d 3 d 2.1, 4.2 C 2 pro-r 1.42 (1) d 4 m 13., 4.2, C 2 2 pro-s 1.5 (1) d 4 m * C 2 3 pro-r 2.09 (1) d 4 m 3.* C 2 3 pro-s 0.9 (1) d 3 ψ-d , 5.0 C 2 2. (1) d 2 d 2., 4.2 C 7 pro-r 1.32 (1) d 4 ψ-d 4., 4.4, 3.7, 2.1 C 2 7 pro-s 2.25 (1) d 4 ψ-d 4 4.4, 4.2, 3.7, 0. C 2 pro-r 2.34 (1) d 3 ψ-d 3 4.4, 3.7, 4.5 C 2 pro-s 2.11 (1) d 3 m 4.4* C (1) d 2 d 2 9.9,.5 C 11 pro-r 1. (1) d 2 d 2 * C 2 11 pro-s 1.1 (1) d 2 d 2 * C (3) - C 3 pro-e 4. (1) d d 1.2 C 2 pro-z 4.97 (1) d d 1.2 C (3) - C (3) - C 3 Table 2. Proton ignal and coupling of caryophyllene oxide. * Indicate that a full et of coupling contant could not be determined due to inufficient reolution on the 1D 1 pectrum. ** C = methine; C 2 = diatereotopic methylene (+ exo-methylene)

4 Carbon Shift (ppm) Bonded Proton() Environment C- Coupling* a C {A, B}, D, {E, G}, {F, N}, I, {J, L} b A, B C 2 D, {E, G} c 3.9 C C {E, G}, {F, N}, {, R}, d C C, {F, N}, {, R}, {K, M}, e 50. I C {B}, D, {, R}, {J, L}, {K, M} f 4.9 D C {A, B}, {E, G}, I, {J, L}, {K, M}, P, Q g 39.9 J, L C 2 {A, B}, D, P, Q h 39.3, R C 2 C, I, {K, M}, i C D (weak), I, {J, L}, P, Q j 30.4 F, N C 2 C, {E, G} k 30.1 Q C 3 I, {J, L}, Q l 29.9 E, G C 2 {A, B}, D, {F, N} m 27.4 K, M C 2 D, {, R}, I, J n 21. P C 3 I, {J, L}, R o 17.2 C 3 {, R} Table 3. SQnd MBC coupling data ummary table for caryophyllene oxide. * Brace indicate that either coupling to both diatereotopic proton in a methylene pair i preent or coupling to a ingle proton in one uch pair i viible on MBC.

5 thod of Analyi and Aignment: 1D NMR thod NMR (Appendix 1) a. 24 proton oberved b. potential entry point: 2 doublet ( A, 4.97 ppm; B, 4.) with mall coupling in alkene region - exo-methylene? c. potential entry point: 3 methyl inglet (, 1.20 ppm; P, 1.00 ppm; Q, Q) d. and P peak trength lightly le than Q ome mall coupling for thee peak? e. peak between 2 and 3 ppm - omewhat downfield alkyl ignal - preence of electronegative heteroatom? f. no aromatic proton 13 C NMR (Appendix 2) a. 15 carbon b. 2 plauible alkene peak (, ppm;, ppm), one of which i weak - an internal p 2 carbon? agree with exo-methylene uggetion (ee 1.1.a). c. 3 more weak/moderately weak carbon peak (C d, 0.0 ppm; C e, 50. ppm, C i, 34.2 ppm) - 3 quaternary center? d. 2 peak in region ~0 ppm - poible carbinol carbon? - agree with uggetion of electronegative atom (ee 1.1.d). e. no carbonyl peak f. DEPT may be neceary - 3 very cloe peak (, 30.4 ppm; C k, 30.1 ppm,, 29.9 ppm) 3. DEPT (Appendix 3) a. reolve confuion in region ~30 ppm - and are likely methyl (trong ignal, poitive phaing); C k i methylene (negative phaing) 4. Tentative Concluion from 1D a. partial molecule formula - C b. even number of would require even number of N, or any number of c. if oxygen preent, ID = = 4; one alkene implied by exomethylene; no carbonyl or other alkene preent ugget that 3 ring may exit 2D NMR thod: 1. SQC (Appendix 4) ee pectra for pecific aignment of A - R and -C o a. 3 methyl, methylene, 3 methine, and 3 quaternary center total b. further confirmation of exo-methylene A and B on ame carbon ( ) c. C, D, and I confirmed a methine, while everal iolated peak with

6 integration of 1(for E, F, M, and N ) are in fact diatereotopic methylene d. carbon ~ 30 ppm can be cleared up completely definitely 2 methylene and a methyl e. R, an apparent multiplet partially buried under Q at 0.9 ppm, i definitely not an impurity but rather a methylene on C h, along with hift are very well eparated (0.9 and 2.09 ppm), implying ome intereting electronic effect at work f. aumed quaternary C (C d, C e, and C i ) confirmed a uch no cropeak 2. MBC (Appendix 5) pleae note: (#) after each entry below correpond to a tructure in Figure 1 on next page, howing gradual olving of connectivity. a. The exo-methylene carbon ( ) i coupled to proton on two eparate carbon, C f and indicate proton alpha to the alkene functionality (1). b., aide from proton on and C f, i alo coupled to proton, which are not coupled to the C f nucleu (2). c. i only coupled to one other proton than thoe previouly identified: C on C c (3). d. ther proton coupled to C c include thoe found on C h and C o. Additionally, C d, a quaternary center, i coupled to proton on, C c, C h, and C o along with proton on another carbon, C m. Since the connectivity of the -C c fragment ha been etablihed, the poition of C d can be etablihed (4). e. With thi information, C o can be connected to either C c (5a) or C d (5b). owever, the fact that C o i only coupling to proton on C h, which couple to C d but not C c eliminate the poibility of 5a. Thi alo allude to C h -C d connectivity (). f. C h i additionally coupled to proton on C e and C m. owever, the fact that C e i coupled to all the ame proton a C m but ome additional proton, including the proton on C f and, not only lead to the etablihment of C e and C m connectivity, but evidence the cloure of a nine-membered ring. Thi i upported by the coupling of alkenyl, which couple to the proton of C e (7). g. The four unconnected carbon remaining (C g, C i, C k, and C n ) can only adopt one tructural motif. Becaue C k and C n both contain methyl inglet in the 1 NMR, and C i i a quaternary carbon, i the only poible fragment. All proton on thee carbon couple to one another, upporting thi hypothei. h. The only quetion that remain i how fragment i attached to fragment 7: either 9a or 9b. Either way, a four-membered ring i neceary. The fact that C g couple to proton on C f but not C e, ugget 9b over 9a. i. The current [7.2.0]bicycloundecane core account for all the carbon but account for only 3 degree of hydrogen deficiency not the 4 uggeted by our tentative molecular formula. Additionally, all carbon currently adhere to the octet rule except C d and C c. Thi information, combined with the fact that C c and C d along with their bonded hydrogen are coniderably

7 dehielded lead to the etablihment of an epoxide functionality acro thi C-ond, etablihing the full connectivity of the unknown (). D E G D E G D E G C D E G C C f C f C f C c C f C c C d A F N F B A B A B N A F B 4 N D E G C R C f C c C h C d F N C o A B D E G C C f C c C d F N C o A B 5a D E G c Co C f C c C d F N A B 5b K M C o I C m C d C e C h R C c C C E f C G l C a D F N A B 7 9a K M C o L I C m C d C C e C g h J P R C c C P C N C E C f C G i l P C C a Q D F N Q Q A B 9b Q Q K M C o Q C k I C m C P d C C e C i h P C n P R C c C J C E C f C G g l C a L D F N A B Q P P P Q C n J C k L Q C i C g C 2 Figure 1. Logical aembly of tructure baed on MBC data.

8 With connectivity etablihed it become convenient to abandon the A - R and -C o naming ytem and witch to numbering carbon on our tructure: C 2 13 Figure 2. Structure howing connectivity of unknown compound. 3. gcsy (Appendix ) a. Confirm connectivity etablihed by MBC. f particular note i that there are two nearly iolated pin ytem apparent on the gcsy one can chain-walk from trong coupling to trong coupling from the 2 11 through, to 1, to both 2, and o on down to the 3 methyl proton on C 13, and imilarly one ee trong coupling among -, but there i only weak coupling between the 2 and one of the 2, and there i imilarly weak coupling between and 13, which ugget that thee are not 3 J but rather longer-range coupling and corroborate our tructure. b. can be ued to determine relative tereochemitry. We aume arbitrarily that 1 i up and that C 1 tereochemical aignment i then R: C 2 c. auming for now that all methylene around 9-membered ring will rotate into a roughly taggered conformation to minimize energy, we then gue that 1 will couple more trongly to 2R, which will be anti to 1 wherea 2S i likely yn. gcsy how 1 coupling more trongly to peak at 1.42 than to peak at 1.5 ppm, implying that 1.42 i 2R : 5

9 S R C 2 d. 2R couple more trongly to one 3 (2.09 ppm) than to the other (0.9); again, tronger coupling probably to anti, o 2.09 i likely 3R and 0.9 i 3S. e. 3R i far downfield compared to 3S the effect of interaction with the epoxide? We gue that dehielding i through-pace effect and i up, cloer to 3R than 3S, which put C 13 down and make C 4 R: C 2 f. couple with 13. Thi i a 4 J and therefore probably a W-coupling, which put up and make C R: C 2 g. couple about equally with both 7 (ee volume integral). owever, coupling contant oberved on 1D 1 are clearly very different, with one J value ~11 z and the other ~4 z. 4 z i more conitent with a dihedral angle of 0 o, while 11 z i more conitent with ~ o. Viual inpection of the 1D 1 how wider plitting only in 7 at 1.32 ppm, implying that thi proton i anti and theforefore 7R, while the other 7 at 2.25 ppm ha nearly contant coupling contant (~4 z) and i therefore more likely yn and 7S. h. 7S couple more trongly with at 2.11, o 2.11 anti, o S, making 2.34 R. i. ha trong coupling with 1, implying tran ring junction and making C

10 S: C 2 j. couple more trongly to 11 at 1., o 11R (anti), making S. k. 11S ha cropeak with 15, implying W-coupling. 11S i down, uggeting that C 15 i up. C 1 i likely down: C 2 Confirmation of Structure, Including Stereochemitry Molecular modeling in Spartan and Chem3D of propoed relative tereochemitry how bond angle reaonably conitent with taggered aumption made in CSY analyi. Alo, lone pair on epoxide i appropriately poitioned for interaction with 3R. (-)-caryophyllene oxide, a natural product derived from chamchwi, a flowering plant, happen to have the ame abolute tereochemitry a the tructure we propoe. It i commercially available from Aldrich. The enantiomer doe not appear to be commercially available. Comparion by brief inpection with 1D 1 pectra from Aldrich how a good match. Thu we propoe that our unknown i, indeed, (-)-caryophyllene oxide