J. Org. C h e m . 1992,57,804-811
804
Synthesis and 13CNMR Spectral Data of 4a,5a- and 4@,5@-Epoxyeudesmanolides. Configuration and y Effect of the Oxirane RingtJ and J. Alberta Marco*vZb
Miguel Carda,2aJuan F.
Departamento de Quhnica Orgdnica, Colegio Universitario de Castellbn, E-12080 Castellbn, Spain, and Departamento de Quimica Orgdnica, Facultad de Ciencias Q u h i c a s , Universidad de Valencia, E-46100 Burjassot, Valencia, Spain Received June 10, 1991 (Revised Manuscript Received October 15, 1991)
The epoxide eudesmanolides 14-21, which constitute epimeric pairs with respect to the confiiation of the oxirane ring, have been synthesized in a stereochemically unambwoue way. Comparison of their '9c NMR spectra with thoee of the parent olefins 10-13 does not, however,reveal any significant correlation between the configuration of the oxirane ring and the shifts undergone by the signals of the y carbon atoms C-1/C-2/C-l/C-9/C-14. object of various theoretical a p p r o a c h e ~ . ~ t ~ l - ~ ~
Introduction In the course of our current investigation on terpene natural products, we have been confronted with the problem of assigning a configuration to an epoxide ring condensed with a cyclic ~ y s t e m . ~Aside from chemical methods, NMR spectroscopy constitutes the most convenient method of solving such problems. In most instances 'H NMR is used for the structural analysis of oxiranes,4+ but NMR spectroscopy of other nuclei also provides useful information. While 1 7 0 N M R studiedoon this class of compounds are still scarce, 13C NMR spectroscopic research on epoxides has given rise to a considerable number of p ~ b l i c a t i o n s . ~ ~ ~The * ~interest ~ ~ ' ~ - has ~ focused not only on the NMR signals of the epoxide carbons themselves (a,counting from the oxygen atom), but also on the influence of the heterocyclic ring on the 13C NMR signals of the spatially proximate 8, y, and 6 carbon atoms.
c. X
\ c,
4* A
B
As mentioned above, no general agreement has been (1)Part 3 of a eeriea on 'Bc NMR spectroecopyof sesquiterpenes. For parte 1 and 2,see: (a) Marco, J. A.; Carda, M. Magn. Reson. Chem. 1987, 25,628-634. (b) Marco, J. A.; Carda, M. Magn. Reson. Chem. 1987,25, 1087-1090. $2)(a) Colegio Universitario de Castelldn. (b) Facultad de Ciencias Quunicas, Universidad de Valencia. (3)(a) Marco, J. A.; Barber& 0.;Lex, J.; De Clercq, P.; De Bruyn, A. J. Not. Prod. 1989,52,547-553.(b) Marco, J. A.; Sam, J. F.; Falcd, E.; Jakupovic, J.; Lex, J. Tetrahedron 1990,46,7941-7950. (4)Tori, K.; Komeno, T.; Nakagawa, T. J. Org. Chem. 1964, 29, 1136-1141 and references cited therein. (5) Tori, K.; Aono, K.; Kitahonoki, K.; Muneyuki, R.; Takano, Y.; Tanida, H.; Tsuji, T. Tetrahedron Lett. 1966,2921-2926. (6)Herz, W.; Hall, A. L. J. Org. Chem. 1974,39,11-14. (7)Kleinpeter, E.;K h , H.; M m t g d t , M. Org. Magn. Reson. 1977, 9,312-317. (8) (a) Paquette, L. A.; Friatad, W. E.; Schuman, C. A.; Beno, M. A,; ChrJstaoh. G. G. J. Am. Chem. SOC.1979.101.4645-4655 and reference8 therein: (b)Paquette, L. A.; Can, R. V. C.;Ahold, E.; Clardy, J. J. Org. Chem. 1980,45,4907-4913. (9)Chriatol, H.; Laffite, C.; Pllnat, F.; Renard, G. Org. Magn. Reson. 1981,17,110-117. (10)(a) Iwamura, H.; Sugawara, T.; Kawada, Y.; Tori, K.; Muneyuki, R.; Noyori, R. Tetrahedron Lett. 1979,3449-3452. (b) Monti, J. P.; Faure. R.: Sauleau. A.: Sauleau. J. Mum. Reson. Chem. 1986.24.15-20. (ll)(a) Tori, K.;Komeno, T.; Sa&€, M.; Septe, B.; Delp&h, B.; Ahond, A.; Lukaca, G. Tetrahedron Lett. 1974,1157-1160.(b) Sangar6, M.; Septe, B.; Bbrenger, G.; Lukaca, G.; Tori, K.; Komeno, T. Tetrahedron Lett. 1977,699-702. (12)Zimmerman, D.; R e i , J.; Coste, J.; PlBnat, F.; Christol, H. Org. Magn. Reson. 1974,6,492-493. (13)(a) Eaaton, N.R., Jr.; Anet, F. A. L.; B m , P. A.; Foote, C. S. J. Am. Chem. Soc. 1974,96,3945-3948.(b)Servis, K.L.;Noe, E. A,Easton, N. R., Jr.; Anet, F. A. L. J. Am. Chem. Soc. 1974,96,4185-4188. (14)Davies, S. G.; Whitham, G. H. J. Chem. Soc., Perkin Trans. 2 1976,861-863. (15)Pauleon, D. R.;Tang, F. Y. N.; Moran, G. F.; Murray, A. 5.;Pelka, B. P.; Vasquez, E. M. J. Org. Chem. 1978,40,184-186. (16)Shapiro, M.J. J. Org. Chem. 1977,42,1434-1436. (17)Hevesi, L.; Nagy, J. B.; Krief, A.; Derouane, E. G. Org. Magn. Reson. 1977,10, 14-19. (18)(a) Leaage, S.;Perlin, A. S. Can. J. Chem. 1978,56,3117-3120. (b) Holland, H. L.; Diakow, P. R. P.; Taylor, G. J. Can.J. Chem. 1978, 56,3121-3127. (19)Delmond, B.; Papillaud, B.; Valade, J.; Petraud, M.; Barbe, B. Org. Magn. Reson. 1979,12,209-211. (20)Zefirov, N. S.;Kasyan, L. I.; Gnedenkov, L. Y.; Shashkov, A. S.; Cherepanova, E. G. Tetrahedron Lett. 1979,949-950. (21)Shuin, U. Tetrahedron Lett. 1979,1833-1836. (22)Matoba, Y.;Kagayama, T.; Ishii, Y.; Ogawa, M. Org. Magn. Reson. 1981,17,144-147.
6
For stereochemicalassignments, the emphasis until now has been on the y effect of the epoxide ring, i.e. the effect produced by the threemembered heterocycle on the N M R signal of the y carbon atom. While much has been published concerning the origins and mechanisms of the y effect,*% no defiitive conclusions of a general structural application have been reached. The core of the problem lies in the fact that the y effect is not intrinsically homogeneous. As a matter of fact, conceptual differences have been established between the so-called y-syn (y gauche) effect and the y-anti effect, these names being related to the dihedral angles in the fragment X-C,-C,g-C! (see illustration). The y-syn effect is usually shielding and is observed in conformational gauche dispositions, such as that depicted in A (dihedral angle from 0 to ca.60°), where X may be either a carbon or a heteroatom. Interestingly, a hydrogen atom must be present on the y carbon atom in order for an upfield (shielding) y-syn effect to be observed, otherwise downfield (deshielding) shifts occur. Different explanations have been offered to account for this spectral behavior.30*33 As for the y-anti effect, which may also be both shielding and deshielding,it is associated with conformational, antiperiplanar orientations such as B (dihedral angle ca. 180O). This effect has also been the 'Dedicated to the memory of the late Prof. F. Gaviiia, deceased May 1990.
0022-3263/92/1951-0804$03.00/0
c,
c1
X
0
P
c3 '
x
Q
1992 American Chemical Society
J. Org. Chem., Vol. 57, No. 3, 1992 805
4a,5a- and 4/3,5/3-Epoxyeudesmanolides
reached as yet regarding the exact nature of the factors Scheme I. Synthesis of the a-Epoxides 7-9" which contribute to the y effect, nevertheless, it has beX X come clear that, aside from the dihedral angle X-C,-C+, many other molecular features may play an important role in determining both the size and sign (upfield or downfield) of the observed overall effect. These features include the nature of the atom X,29 the bond angles and lengths30bJ2in the carbon chain which connects X and Cy, the degree of substitution31within this carbon chain, linear electric field effects,= and n*x-uH(y)orbital 0verlap.3~The extreme diversity of these factors advises 9 X=H,@OAc 6 X = H. pOAc against the indiscriminate application of y effects to stereochemical assignments.3l "(a) m-CPBA, CH2C12, 0 "C; (b) NaBH4, MeOH, -50 O C ; (c) PCC, NaOAc, CH2C12,rt. The y effect has also been used in the structural analysis of epoxides. It has been claimed that the shifts of the 13C NMR signals produced by the introduction of the oxirane epoxide eudesmanolides 2 and 3 (R = H, OTBDMS), moiety into mono- or polycyclic frameworks can be used which were obtained by peracid epoxidation of 1 (R= H, to determine configurational assignmentsunambiguously. OTBDMS). In the absence of other stereochemical One example of this is the shift of the NMR signal of the criteria, the a-epoxide configuration was assigned in each bridge carbon atom in norbornane d e r i v a t i v e ~ ' ~ Jand ~ * ~ * ~ case to the major lactone 2 formed during the epoxidation structurally related compounds78M3after the introduction (preferential attack from the less hindered side of the epoxide oxygen. A similar effect had been previously of the double bond). After measuring the 13C NMR observed in cyclopropane analogues.36 In polycyclic spectra, it became evident that the signals of the carbon compounds containing six-membered rings, like steroid1lJSb atoms C-1, C-2, C-7, (2-9, and (2-14 (7 with respect to the and diterpene epoxide^,^^^^^ characteristic upfield shifts oxirane ring) did not show the expected systematic shifta with respect to the parent olefin are observed in the NMR in relation to the correspondingsignals in the parent olefm signals of those y carbons having an axial hydrogen syn 1. According to the aforementioned syn axial y hydrogen relative to the epoxide oxygen. In contrast, the signals of rule,ll the epoxides 2 should have shown upfield shifta in y carbon atoms lacking this feature do not undergo sigthe NMR signals of C-1, C-7, and (2-9, taking lactone 1 as nificant shifts. a reference. In the case of 3, however, such upfield sh& should have occurred only in the signals of C-2 and perhape
L
(2-14.
Several years ago we synthesized37 and measured the
NMFt spectra' of a number of sesquiterpene lactones with eudesmane framework. Among these were the pairs of (23) Christl, M.; Leiniiger, H.; B m , E. J. Org. Chem. 1982, 47, 661-666. (24) Schneider, H.-J.; Agrawal, P. K. Magn. Reson. Chem. 1986,24, 718-722.
(25) Gar&-Granados, A.; Martbez, A.; Onorato, M. E.; Santoro,J. Magn. Reson. Chem. 1986,24,853-861. (26) Levy, G.C.; Nelson, G.L. Carbon-I3 Nuclear Magnetic Resonunce for Organic Chemists; Wiley Interscience: New York, 1972; Chapter 3. (27) Kalinow&, H.-0.; Berger, S.;Braun, S.I3C-NMR Spektroekopie; Georg-Thieme Verlag: Stuttgart, 1984, Chapter 3. (28) Breitmaier, E.; Voelter, W. Carbon-13 NMR Spectroscopy;VCH Verlagageaellschafk Weinheim, 1987; Chapter 3. (29) Eliel, E. L.; Bailey, W. F.; Kopp, L. D.; Willer, R. L.; Grant, D. M.; Bertrand, R.; Chrieteneen, K. A.; Dalling, D. K.;Duch, M. W.; Wenkert, E.; Schell, F. M.; Cochran, D. W. J. Am. Chem. SOC.1976,97, 322-330. (30) (a) Beierbeck, H.; Saunders, J. K. Can. J . Chem. 1976, 54, 632-641. (b) Beierbeck, H.; Saunders, J. K. Can. J. Chem. 1976, 54, 2985-2995. (31) Ayer, W. A.; Browne, L. M.; Fung, S.;Stothers, J. B. Can. J. Chem. 1976,54,3272-3275. (32) Duddeck, H.; Klein, H. Tetrahedron 1977,33,1971-1977. (33) Schueider, H.-J.; Hoppen, V. J. Org. Chem. 1978,43,3866-3873. (34) Forrest, T. P.; Webb, J. G . K. Org. Magn. Reson. 1979, 12, 371-375. (36) Quarroz, D.; Sonney, J.-M.; Chollet, A.; Florey, A.; Vogel, P. Org. Magn. Reson. 1977,9,611-617. (36) Tori, K.; Ueyama, M.; Tsuji, T.; Mataumura, H.; Tanida, H.; Iwamura, H.; Kuehida, K.; Niahida,T.;Satoh, S.Tetrahedron Lett. 1974, 327-330. (37) (a) Carda, M.; A m 6 , M.; Marco, J. A. Tetrahedron 1986, 42, 3655-3662. (b) Marco, J. A.; Am6, M.; Carda, M. Can. J. Chem. 1987, 65, 630-636. (c) Marco, J. A.; Carda, M. Tetrahedron 1987, 43, 2523-2532.
R
-
0
0
21
0 H
R *
0
0
k
Surprisingly, appreciable upfield shifts (from ca. -1.5 to +3.5 ppm) in the signals of C-1, C-2, C-7, C-9, and C-14 were observed for both 2 and 3.'" Moreover, as the size of these shifts did not significantly differ from the a-to the &epoxides,they could not be accurately correlated with the configuration of the oxirane ring. The question of whether thiswas a single case or if these observationscould be extended to other pairs of diastereoisomeric epoxides presented iteelf, for should the latter prove to be the case, it would clearly show that the syn axial y hydrogen rule cannot be universally applied to configurational assignments. We therefore decided to synthesize other pairs of diastereoisomeric epoxy lactones with unambiguously defined stereochemistry in the oxirane ring. The four epimeric pairs of lactone epoxides 14-21 (see below) were chosen for synthesis due to the ready availability of the natural eudesmanolide 4.% Subsequent examination of (38) (a) Sam, J. F.; Marco, J. A. Liebigs Ann. Chem. 1990,541-545. (b) Ruetaiyan, A.; Bamonieri, A.; Raffatrad, M.; Jakupovic, J.; Bohlmann, F. Phytochemistry 1987,26,2307-2310.
806 J. Org. Chem., Vol. 57, No.3, 1992
Carda et al. Table I. *% NMR Data of Lactones 10-21°
carbon 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
lob
11 35.50 17.85 33.12 128.24' 140.45' 75.98 39.65 26.85 76.96 38.76 41.02 179.26 9.41 18.12 20.05
33.95 17.74 32.57 128.24 140.11' 75.66 41.43 31.78 213.40 48.37 40.71 178.33 9.71 26.21 20.00
OR
12 35.09 17.55 32.98 127.45' 140.85' 75.60 39.37 23.76 78.38 37.54 40.87 178.91 9.30 19.46 19.95 170.65 21.08 (OW
13 36.06 18.06 33.34 128.W 140.W 76.00 39.52 27.73 77.29 39.30 41.02 179.28 9.40 18.48 20.04 6.97 5.26 (OSiR3)
14 27.33 14.69 20.35 63.91 66.90 77.42 39.13 34.02 211.31 47.09 40.21 177.81 9.42 20.87 19.99
16 29.62 14.88 27.63 63.04 65.09 78.59 37.58 27.06 73.69 37.85 40.19 178.51 9.15 13.45 20.03
16 29.39 14.63 27.38 63.06 64.68 78.35 37.37 23.83 75.65 36.83 40.10 178.20 9.09 14.63 19.92 170.44 20.99
17 30.05 15.12 27.92 63.12 65.26 78.72 37.47 27.81' 74.12 38.34 40.21 178.59 9.18 13.73 20.14 6.95 5.16
(OAc)
(OS&)
18 34.11 16.10 32.27 61.85 65.11 80.73 36.73 32.98 210.37 47.90 38.09 176.91 10.13 18.62 19.95
19 33.30 16.00 31.70 64.29 64.29 79.19 37.91 26.21 72.39 38.52 41.02 178.70 9.19 16.25 21.42
20 33.33 16.03 31.58 63.87' 64.W 78.83 37.64 23.38 74.09 37.49 40.83 177.79 9.39 17.65 21.54 170.65 21.00
21 33.21 16.34 31.84 64.10 64.10 78.84 37.92 27.43 73.10 39.29 41.16 177.95 9.36 16.73 21.88 6.92 5.23
WAC)
(OS&)
'At 50 MHz in CDC$ (25 "C). The b values (parts per million downfield from Me4Si) are referenced to the center signal of the solvent triplet at 6 77.00 ppm. Data from ref 38a. CThesignals with this superscript may be interchanged within the same column.
the '3c NMR spectra of these epoxides should then allow us to assew the utility of the oxirane 7 effect for configurational assignments. X
Scheme 11. Synthesis of the a-Epoxides 14-17O X
Y
X
rty
m
rty
0
14
X=O
18
X=O
15
X=H,BOH
19
X=H,aOH
16
X=H,sOAc
20
X=H,pOAc
17
X = H, BOSiEt,
21
X = H, uOSIEt,
Synthesis of Epoxy Lactones In contrast to l,37alactone 4 yielded only one epoxide 7 by peracid epoxidation, with no trace of the formation of a second isomer. The hydroxy and acetoxy lactones 5 and 6, obtained by isolation from the plant and/or by chemical transformation of 4 (Scheme I), displayed similar behavior and each gave a single epoxide 8 and 9, respectively, after peracid treatment. All three epoxides were initially thought to belong to the a series, as inspection of molecular models indicated that the a side of the double bond was much less hindered. Since the direct preparation of the Bepoxides from the parent compounds 4-6 did not appear to be it was reasoned that epoxidation from the upper side of the double bond would occur if the axially oriented 6, oygen atom (eudesmane numbering) could assist the reqwred oxygen transfer from the appropriate reagent by means ofchelation. This was not expected to happen in lactonea 4-6 themselves, but rather in the corresponding hemiacetals or diols, derived from the lactones by reductive opening. Since any reductive treatment of compounds 4-6 would most likely affect the conjugated double bond the synthesis of the two epimeric series of epoxides was not performed with the natural lactones 4-6, but with the respective ll,l&dihydro derivatives 10-12, obtained as depicted in Scheme II. Like their precursors 4-6, lactones 10-12 gave rise to single epoxides 14-16 by peracid treatment (Scheme II). For the same reason as mentioned above, they were assumed to be the a-epoxides. (39) Attempta to add BrOH to the tetrasubstituteddouble bond were unsuccessful.
14
X=O
15
X =H,rOH
16
X =H,rOAc
17
X = H, pOSIEt,
(rd.3&) 11
13
X=H,pOH
X = H, POSiEt, 6
(a) m-CPBA, CH2C12,0 "C; (b) EGSiCl, EGN, DMAP, CH2C12, rt; (c) NaBH4, MeOH, -20 "C; (d) PCC, NaOAc, CH2C12,rt.
Scheme 111. Synthesis of the &Epoxides 18-2lU OSIEt3
13
n
23
(a) LAM4, THF, rt; (b) m-CPBA, CH2C12,0 "C; (c) t-Bu02H, VO(au&, benzene, rt; (d) PCC, CH2C12,rt; (e) aqueous HOAc/ THF, 45 "C; (0 AQO, pyridine, DMAP,rt.
Scheme 111displays the synthesis of the required Bepoxides. The free hydroxyl function of lactone 11 was first p r 0 t e d e d ~ 9as~the ~ txiethylsilyl derivative 13 (Scheme II). Attempts to reduce it to the corresponding hemiacetal42
-
(40)The silylation was intended to protect the SOH group in the latter oxidation step 23 21, as well as to improve the solubility of the substrate for the Sharpleee reaction 22 23. (41)While the more labile trimethylsilyl group did not survive the subsequent reaction conditions, the TBDMS group could not be introduced, as lactone 11 did not react with either TBDMSCl or TBDMSOTf.
-
J. Org. Chem., Vol. 57, No.3, 1992 807
4a,5a- and 4/3,5/3-Epoxyeudesmanolides
Table 11. Compared Chemical Shift Differences in Some 'H and 1wNMR Signals for Epoxide/Olefin Pairso atom H-7 H-9 H-14 c-1 c-2 c-7 c-9 C-14 ~fj,,,,,
- fjohk
14-10 0.22
-
0.03 -6.62 -3.05 -2.30 -2.09 -5.34
a-epoxides 16-11 16-12 0.23 0.22 0.29 0.24 0.05 0.05 -5.88 -5.70 -2.97 -2.92 -2.07 -2.00 -3.27 -2.73 -4.67 -4.83
17-13 0.25 0.30 0.05 -6.01 -2.94 -2.05 -3.17 -4.75
&epoxides 19-11 20-12 0.02 0.08 0.38 0.27 0.05 -0.03 -1.76 -2.20 -1.52 -1.85 -1.73 -1.74 -4.29 -4.57 -1.81 -1.87
18-10 0.21
-
-0.04 0.16 -1.64 -4.70 -3.03 -7.59
21-13 0.01 0.36 0.03 -2.85 -1.72 -1.60 -4.19 -1.75
(ppm): positive (negative) values denote downfield (upfield) shifta.
were unsuccessful, but lithium aluminum hydride reduction gave the diol 22 in fairly good yield. Sharpless reaction gave a single epoxide 23, which was assigned the 6 conNot unexpectedly,44peracid epoxidation of 22 yielded the same epoxide. PCC oxidation of 23 gave lactone 21 in 49% yield. This lactone proved to be different from compound 17, obtained by m-CPBA oxidation of 13 (Scheme II), thus confirming the idea that the latter reagent gives rise to a-epoxides. Deprotection with aqueous acid4 yielded hydroxy lactone 19, which was then transformed into 18 and 20.
Results and Discussion Table I summarizes the 13C NMR spectral data of lactones 10-21 (thoee of lactones 4-9 and of compounds 22-23 are given in the Experimental Section). The lH signals were first assigned through their characteristic chemical shifts and coupling patterns (the signal of H-15 was unambiguously differentiated from that of H-14 because of the NOE observed between H-15 and H-6). The '3c signals were then assigned with the aid of two-dimensional onebond heteronuclear correlations. In two casea (compounds 16 and 18) a heteronuclear correlation modulated by long-range couplings (COLOC? was also performed. This enabled the assignment of the quaternary epoxide signals (C-4 and C-5) since only the latter carbon showed correlations with both H-6 and H-14. Other long-range correlations (C-9/H-14, C-10/H-14, C-4/H-15) further served to confirm the assignments of the signals from H-14 and H-15. Table I1 shows the chemical shift differences for the 7 carbons ((3-1, C-2, C-7, (2-9, and C-14) between the respective epoxides (a or 8) and the parent olefins, as well as the chemical shift differences for some hydrogen atoms (H-7, H-9, and H-14). It is worth noting that all of the aforementioned carbon atoms underwent appreciable upfield shifts after the introduction of the oxygen atom, regardless of the stereochemistry of the oxirane ring. This situation, which closely resembles that observed in our previous examples? differs from the literature predictions specified above. It is also significant that the epoxidation shifts of some lH signals do not coincide with what might be expected due to the steric compression effect of the oxirane ring. The signal of the angular methyl H-14, for
Table 111. Distances (in Angstroms) between the Epoxide Oxygen and the Indicated Hydrogen Atomso &Hi, 0-H, GH, @Hg a-Epoxides
(I
7 8 14 18
2.639 2.676 2.666 2.664
18 19 24b 25*
3.790 3.780 3.784 3.765
~
(42) For the uae of a hemiacetal to control the steric course of a
Sharplees oxidation, see: Danishefsky, S.; Hirama, M.; Gombatz, K.; Harayama, T.; Berman, E.; Shuda, P. F. J. Am. Chem. SOC. 1979,101,
7020-7031. (43) Sharpleas, K. B.; Verhoeven, T. R. Aldrichimica Acta 1979,12, 63-74. (44) Kishi, Y. Aldrichimica Acta 1980,13,23-30. (45) Desilylation with tetra-n-butylammoniumfluoride produced partial spherization at C-11. Side reactions during deeilylations with n-Bu,NF due to the basicity of the reagent are well precedentd Corey, E. J.; Venkateewarlu, A. J. Am. Chem. SOC. 1972, 94, 6190-6191. (48) Derome, A. E. Modern NMR Techniques for Chemistry Research; Pergamon Press: Oxford, 1987; Chapter 9.
@-Epoxides 2.782 2.708 2.771 2.799
3.676 3.302 3.120 3.170
2.749 -
4.300 4.337 4.417 4.336
-
2.773
4.123
-
4.623
Calculated with MACROMODEL. Not synthesized (see text).
instance, remains practically unaffected by the presence (and the configuration) of the epoxide. Furthermore, the signal of H-9 (a axial) undergoes even greater downfield shifta in some &epoxides than in their epimeric counterparts (Table 11). Due to the importance of the aforementioned geometric aspects (bond lengths and distances, dihedral angles, etc.) in determining the magnitude of these chemical shifts, it seemed appropriate to have an approximate knowledge of the actual shape in solution of the molecules under study. The coupling constants of the hydrogen atom H-6 to H-9 and H-11 are easily measurable in their respective 'H N M R spectra (Experimental Section). Their values give a partial view of the molecular conformation,at least that of the right-hand cyclohexane ring. Because there is a great deal of overlapping among the hydrogen signals of the lefbhand ring, however, a conclusion about the shape of this ring could not be obtained from the spectral data. We thus resorted to a computer-assisted conformational analysis of several of the molecules in question via Still's MACROMODELpr0gram.4~ Aside from compounds 7,8,14, 15,18, and 19, we also carried out calculations for the as yet unsynthesized 9, epoxides 24 and 25. The results are n on
wwy 0
24 ~~
3.825 3.838 3.825 3.836
25
summarized in Tables I11 and JY, which contain the calculated values for some selected dihedral angles and interatomic distances corresponding to the lowest energy conformer obtained. The vicinal JHH values given by the ~rogram~'9~ are, for the moat part,in agreement with thoee (47) MACROMODEL version 3.0, W. C. Still, Columbia University. Coupling constanta were calculated in the NMR Analyak eubmode of the program (ref 48). Energy minimizations were performed with the BATCHMIN program (version 3.lc), using the Monte Carlo multiconfomer search (MCMM).
808 J. Org. Chem., Vol. 57,No.3, 1992
Carda et al.
Table IV. Dihedral Angles (in Degrees) in the Fragment OC,C,&a
e> w5*10*1
7 8 14 15 18 19
24 25
e
