1926 J. Org. Chem., Vol. 41, No. 11,1976
Gore and Armitage
(25)(a) J. G.Traynham, E. E. Green, Y.4. Lee, F. Schweinsberg, and C.-E. Low, J. Am. Chem. Soc.. 94, 6552 (1972):(b) P. S.Skell, R. R. Pavlis, D. C. Lewis, and K. J. Shea, /bid., 95, 6735 (1973). (26) S.J. Cristol and R. P. Arganbright, J. Am. Chern. Soc., 79, 3441 (1957). (27)Skell and his c o - ~ o r k e r s * have ~ ~ * ~discussed the question of unsymmetrical and symmetrical bridging and the barrier between bridged and open radicals.
(28)G. A. Russell and H. C. Brown, J. Am. Chem. SOC.,77, 4025 (1955). (29)M. S. Kharasch. W. Hered, and F. R. Mayo, J. Org. Chern., 6 , 818 (1941).
(30)C. S. Marvel and V. C. Sekera, "Organic Syntheses", Collect. VoI. Ill, E. C. Horning, Ed., Wiley, New York, N.Y., 1955,p 366. (31)F. Kurzer, "Organic Syntheses", Collect. Vol. IV, N. Rabjohn, Ed., Wiley, New York, N.Y., 1963,p 937. (32)J. W. Wilt, R. G. Stein, and W. J. Wagner, J. Org. Chem., 32, 2097 (1967). (33)H. R. Billica and H . Adkins, Org. Synth., 29, 24 (1949). (34)I. L. Karle, J. Karle, and K. Britts, J. Am. Chem. SOC.,88, 2918 (1966). (35)G.L. Hardgrove. L. K. Templeton, and D. H. Templeton, J. Phys. Chem.. 72,668 (1968).
Lanthanide-Induced Chemical Shifts and the Relative Stereochemistry of Multistriatin, 2,4-Dimethyl-5-ethyl-6,8-dioxabicyclo[3.2.lloctane William E. Gore*la,b and Ian M. ArmitagelC State University of New York, College of Environmental Science and Forestry, Syracuse, New York 13210, and Section of Physical Sciences, Yale University School of Medicine, New Haven, Connecticut 06510 Received August 28,1975 The 'H NMR spectra of the four diastereomers of multistriatin, 2,4-dimethyl-5-ethyl-6,8-dioxabicyclo[3.2.1]0~tane (la-@, and of frontalin, 1,5-dimethyl-6,8-dioxabicyclo[3.2.l]octane (2), were recorded in the presence of the europium paramagnetic shift reagent d~~-tris(2,2-dimethyl-6,6,7,7,8,8,8-heptafluoro-3,5-octanedionato)europium(II1) [(Eu(fod)s].The binding of Eu(fod)3to each substrate was investigated by comparing observed shift ratios' with those calculated for lanthanide atom positions about each of the oxygen atoms in la-6 and in 2.The calculations indicated that for each of these dioxabicyclo[3.2.l]octanes,substrate binding occurred preferentially at one oxygen atom, and that the location of the lanthanide atom was related to steric hindrance about the two potential binding sites. Comparisons of the observed shift ratios for each isomer of 1 with the calculated shift ratios of all isomers of 1 verified the relative stereochemicalassignmentsfor these isomers. A correlation between the shift reagent binding site and the biological activity of la-S was observed. a-Multistriatin (la),a component of the aggregating The use of LIS data to test proposed configurations or pheromone of the European elm bark beetle, Scolytus mulconformations has been recently re~iewed.*-~ In the case of tistriatus, was identified as 2,4-dimethyl-5-ethyl-6,8-dioxa- monofunctional substrates, bonding occurs between donor bicyclo[3.2.l]octane by spectrometric and synthetic methods.2 atom (X) on the substrate (S) and the lanthanide metal atom The previously reported synthesis yielded the four possible (L), and a set of equilibria exists for L, S, LS, LS2, and perhaps diastereomers (la-&), and these isomers were separated by additional species. This bonding situation is essentially the GLC and were characterized by NMR, ir, and MS.3 The same for a multifunctional substrate if L binds preferentially spectrometric data in combination with a stereospecific synt o one functional group. thesis provided evidence for the assignment of the relative Competitive complexing with multiple donor atoms on the stereochemistry of each of the four diastereomers. substrate molecule has also been revieweds and is of particular importance in this study of bicyclic ketal structures. Similar donor atoms with identical environments should experience identical L-X bonding, and this expectation has been verified by experiment. However, the lanthanide bonding properties of like functional groups with dissimilar environments can differ. Functional groups usually bond preferentially (OH > ketones 2 esters > ethers); however, this bonding trend can be altered as a consequence of steric hindrahce. Such was the la 1s case in a computer-assisted LIS study by Farid et al., who described preferential bonding of tris(2,2,6,6-tetramethyl3,5-heptanedionato)europium(III)to an unhindered ether in the presence of a hindered alcohol group.g Selective binding in substrates that contain two dissimilar ether groups has also been reported.s The lanthanide-induced change in chemical shift for proton 1Y 18 H, (As,) can be calculated from the pseudocontact term of the McConnell-Robertson equationlo Lanthanide-induced shift (LIS) experiments represented a potential and possibly unique method for testing structural ~ 6 ,= K (3 cos2 8, - 11rn-3 (1) assignments for la-6. The objective of this study was to first -~ evaluate the binding of the shift reagent to la-6 and to 1,5- where 8, is the XLH, angle and r is the LH, d i ~ t a n c e . j Didimethyl-6,8-dioxabicyclo[3.2.l]octane, frontalin (Z),and then rect application of this equation to the evaluation of the to compare any definitive evidence relating the structure of paramagnetic shifts assumes the absence of a contact contribution to the observed chemical shifts and that the LS comthe 6,8-dioxabicyclo[3.2.l]octanesto the previous stereochemical assignments for la-6. plex has effective axial symmetry about the L-X bond. Both
J. Org. Chem., Vol. 41, No. 11, 1976
Relative Stereochemistry of Multistriatin
Table I. LIS Data for Frontalin (2)
a
Shift ratiosa
Frontalin
A61/A62 ASl/A63 A61/A64
0.45
2-A
2-8
I
I
1927
0.28 0.27
[L] = 0.016, [SI= 0.70.
assumptions have been shown to apply, particularly in the case of proton shift studies.11-13 The A6, values can be measured from the 6,’ for a single shifted spectrum and 6, for an unshifted spectrum (As, = 6,’ - 6,); however, spectra are usually recorded at several [L]/[S] ratio^.^ One Ab; value is selected as the reference value, and the remaining A6, are related to A6; as the shift ratio A6;/Ab, (calcd) for protons j through n for which observed shift values are available. B,Ziw,((A6;/A6,)obsd - (A6;/A6,)calcd)2 R=[E n + i W n (A6i/A6,)obsd2
Figure 1. Frontalin (2) in coordinate systems A and B depicting the optimum calculated position of the Eu atom.
i \
1
\
112
The agreement factor R is used to compare the calculated shift ratios and the corresponding observed shift ratios for several different locations of L. This process is continued, usually as a computer operation, and L is moved through all space surrounding X. A minimum R value is associated with those positions of L which give the best agreement. The calculation is described as being “relatively insensitive (0.2-0.3 A) to assumed lanthanide position or to error in model coordinates, but sensitive to signal assignments and to substrate stereocherni~try”.~
\
/ I Figure 2. Location of the lanthanide atom with respect to the sub-
strate atoms.
atom with a radius equal to the upper limit of the Eu-0 bond length.5 A set of shift ratios were calculated a t each Eu position, and the calculated values were compared to the observed shift ratios. A maximum limit C, for A6,/A6, calcd - A6;/A6, Results and Discussion obsd was set, and if C, exceeded the limit, the comparison for The binding of tris(2,2-dimethyl-6,6,7,7,8,8,8-heptaflu- that Eu position was discarded. When this condition was oro-3,5-octanedionato)europium(III),Eu(fod)S, to the bisatisfied, the agreement factor R was calculated. functional dioxabicyclo[3.2.l]octanering system was initially The R values in combination with the position of the Eu investigated with a known compound, frontalin @),I4 for atom relative to the substrate molecule provided a basis for the evaluation of a test structure. Minimum R values were regarded as indicators of relatively good agreement particularly where relatively small values were found for a cluster of Eu positions. The location of the Eu atom was examined, and any positions coincident with other atoms in the substrate were eliminated. The possibility of chance agreement cannot 3 be completely eliminated, particularly when a limited number 2 of proton signals can be observed; however, as our data will which four observable proton signals could be unambiguously demonstrate, these criteria provided a basis for consistent assigned. The A6, values for protons 1,2,3,and 4 were meainterpretation of the data. sured, and the A6;/A6, obsd values are given in Table I. No agreement between calculated and observed shift ratios Two separate Cartesian coordinate systems were calculated was obtained for 2 in coordinate system B over the range of (for details see Experimental Section) for the atoms in 2 with R , D, and @ searched, but good agreement ( R reportedby a Japanese group.4 A few other attempts to synthesize samandarine and the ring system have also been reported.& Since there are several established ways to introduce an oxygen function at C-16, the major problem inherent in the synthesis of these alkaloids is in the construction of the bridged oxazolidine system with the correct stereochemistry.
In this paper, the author reports a general procedure for the preparation of the bridged oxazolidines from a,@-unsaturated cyclic ketones and a facile, stereoselective formal synthesis of samandarine (1).
w
".,d
H
