Elucidation of the conformations and absolute configurations of enantiomerically pure tetralin derivatives

MAGNETIC RESONANCE IN CHEMISTRYMagn. Reson. Chem. 37, 53È59 (1999)

Elucidation of the conformations and absoluteconügurations of enantiomerically pure tetralinderivatives

Ga� bor To� th,1 Andra� s Simon,1 Torsten Linker,2 Frank Rebien,2 Ju� rgen Kraus3 and Gerhard Bringmann3*

1 Technical and Analytical Research Group of the Hungarian Academy of Sciences, Institute for General and Analytical Chemistry,Technical University of Budapest, Gelle� rt te� r 4, H-1111 Budapest, Hungary2 Institut fu� r Organische Chemie der Universita� t Stuttgart, Pfaþenwaldring 55, D-70569 Stuttgart, Germany3 Institut fu� r Organische Chemie der Universita� t Wu� rzburg, Am Hubland, D-97074 Wu� rzburg, Germany

Received 9 June 1998; accepted 22 August 1998

ABSTRACT: The enantioselective epoxidation of 1,2-dihydronaphthalenes (2) a†orded optically active tetralinderivatives (3 and 4). The relative conÐgurations and conformational behavior of all products were elucidated bydetailed one- and two-dimensional 1H and 13C NMR methods. The last required stereochemical information, theabsolute conÐguration of 4, attained through comparison of experimental and calculated CD spectra.

1999 John Wiley & Sons, Ltd.(

KEYWORDS: NMR; 1H NMR; 13C NMR; conformational equilibrium; circular dichroism; quantum chemical calculations

INTRODUCTION

Etoposide 1 represents one of the most important anti-tumor drugs for the treatment of lung and testicularcancer.1 In the context of the synthesis of the tetralinsystem of this compound, we developed a convenient

* Correspondence to : G. Bringmann, Institut fu� r Organische Chemieder Universita� t Wu� rzburg, Am Hubland, D-97074 Wu� rzburg,Germany.Contract/grant sponsor : Deutsche Forschungsgemeinschaft ; Contract/grant nymber : Li 556/2-2 ; Contract/grant number : SFB 347.Contract/grant sponsor : Hungarian ScientiÐc Research Fund(OTKA) ; Contract/grant number : T026264.Contract/grant sponsor : Fonds der Chemischen Industrie.

entry to the chiral dihydronaphthalene rac-2, anddescribed the highly diastereoselective oxidation of thedouble bond with singlet oxygen as well as with per-acids.2 More recently, we became interested in an asym-metric version of this methodology by means of akinetic resolution by Jacobsen epoxidation.3 In thepresence of a catalytic amount of a (S,S)-(salen)man-ganese(III) complex, the products 2È4 were isolated withup to 98% ee (Scheme 1).4

However, until now only the enantiomeric excesseswere determined by high-performance liquid chroma-tography on a chiral phase, and the absolute conÐgu-rations were speculative. In this paper, we describe thestructure elucidation, conformational behavior and the

Scheme 1

( 1999 John Wiley & Sons, Ltd. CCC 0749-1581/99/010053È07 $17.50

54 G. TOŠ TH ET AL .

complete 1H and 13C NMR assignments of compounds2È4 and the determination of their absolute conÐgu-rations by circular dichroism (CD) spectroscopy.

RESULTS AND DISCUSSION

NMR spectroscopy

Structure elucidation of 2È4 is based on the NMR spec-tral assignments which were conÐrmed by 1H,1H-COSY, gs-HMQC,5 gs-HMBC,6 phase-sensitiveNOESY7 and 2D semi-selective INEPT8 experiments.The 1H and 13C chemical shifts, characteristic J(H,H)protonÈproton nJ(C,H) carbonÈproton coupling con-stants and NOESY and HMBC responses are sum-marized in Table 1.

The assignment of 2 is straightforward on the basis ofHMQC and HMBC measurements. The H-1 protonmarks the quaternary C-4a and C-8a atoms in theHMBC spectrum and the H-2/C-8a cross peak allowstheir di†erentiation. It has been found previously thatthe chemical shift of H-5 is indicative of the stericarrangement of the 4-phenyl group, since the planes ofthe two aromatic groups are nearly perpendicular,owing to the steric interaction between the equatorial4-phenyl and the fused aromatic ring, resulting in strongshielding of the H-5 proton.9 Considering the relativelysmall value of J(H-3,H-4) \ 8.5 Hz, the participation ofthe conformer in the equilibrium is con-H-3eq ,H-4eqsiderable besides the preferred the con-H-3ax ,H-4axformer.

In the 1H NMR spectrum of 3, the coupling betweenthe H-2 and H-3 protons is 0 Hz, proving their perpen-dicular arrangement. To achieve a pairwise assignmentof the H-1/H-2 and H-3/H-4 doublets, we utilized theNOESY cross peak between 3.93 and 3.19, which estab-lishes the neighboring H-2 and H-3 protons. The

NOESY cross peak between H-1/H-8 proves the assign-ment of the doublet at 7.46 ppm. The remaining aro-matic CH doublet belongs to H-5 (6.56) and its strongshielding is in accordance with the equatorial positionof the 4-phenyl group. Further information about theconformational behavior of this phenyl substituent wasobtained by selective two-dimensional INEPT experi-ments. On the basis of literature data,10 the value ofJ(C-2@,6@,H-4)\ 5.6 Hz coupling proves a coplanararrangement of the H-4 bond and the phenyl. Thephenyl and ester substituents are trans-diequatorialpositioned in the preferred conformation, as followsfrom the coupling constant J(H-3,H-4) \ 12.0 Hz. Forthe determination of the relative conÐguration andstereostructure of isomers 3 and 4, it should be takeninto consideration that the cyclohexene ring is Ñexibleand can occur in form of two rapidly interconvertingtwist-boat conformers, (Scheme 2)A½B

Steric proximity (\4 between H-1 and H-3 atomsÓ)is possible only in the A conformation of 3. The H-1/H-3 cross peak unambiguously veriÐes the relativeconÐguration of this compound (see Fig. 1). A carefulvolume integration of NOESY cross peaks revealed adistance between H-1 and H-3 of 3.85 which is inÓ,good agreement with that of obtained from Dreidingmodel (3.85 For calibration of the volumeÓ).integrationÈdistance correlation, we considered theH-5ÈH-6 distance to be equivalent to 2.48 Ó.

Scheme 2

Figure 1. Section of NOESY spectrum of 3.

( 1999 John Wiley & Sons, Ltd. MAGNETIC RESONANCE IN CHEMISTRY, VOL. 37, 53È59 (1999)

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Table 1. Characteristic 1H and 13C chemical shifts, coupling constants (J, Hz) and NOE and HMBC responses

2 3 4

1H 13C HMBC 1H NOESY 13C 1J(C,H) nJ(C,H-4) HMBC 1H NOESY 3C 1J(C,H) nJ(C,H-4) HMBC

1 6.62 129.1 3 ;4a ;8 ;8a 4.03 2 ;8 52.9 182 4a ;8 ;8a 3.96 8 51.9 181 3 ;4a ;8 ;8a2 5.90 123.7 3 ;4 ;8a 3.93 1 ;3 55.5 184 3.0 3 ;4 3.96 3 56.0 183 7.3 3 ;43 3.66 48.6 2 ;CxO 3.19 1,2 ;4 ;2@ ;6@ 48.0 131 7.0 2 ;4 ;1@ ;CxO 3.74 2 ;4 ;2@ ;6@ 46.3 133 5.0 1 ;2 ;4 ;4a ;

1@ ;CxO4 4.60 45.8 2 ;3 ;4a ;5 ;8a ; 4.33 3 ;5 ;2@ ;6@ 43.0 132 2 ;3 ;4a ;1@ ; 4.73 3 ;5 ;2@ ;6@ 45.7 131 2 ;3 ;4a ;5 ;8a ;

1@ ;2@,6@ ;CxO 2@,6@ ;CxO 1@ ;2@,6@ ;CxO4a È 136.2 È 139.0 È 7.4 È 135.2 È 6.85 6.84 128.3 7 ;8a 6.56 4 ;6 ;2@ ;6@ 128.3 162 1.9 7 ;8a 7.11 4 ;6 ;2@ ;6@ 130.8 160 4.7 7 ;8a6 7.09 128.0 4a ;8 7.15 128.7 160 4a ;8 7.32 129.2 161 4a ;87 7.17 127.0 5 ;8a 7.21 126.4 163 5 ;8a 7.30 127.1 162 5 ;8a8 7.12 126.5 1 ;4a ;6 7.46 1 ;7 129.5 161 1.0 1 ;4a ;6 7.52 1 ;7 129.9 161 1 ;4a ;68a È 132.5 È 131.1 È 1.8 È 132.4 È 3.9CxO È 173.5 È 172.7 È 3.3 È 172.2 È 4.8OMe 3.59 52.0 3.59 52.1 148 3.70 52.3 1451@ È 142.8 È 140.1 È 6.3 È 145.4 È 8.02@,6@ 7.19 128.6 4 ;4@ 7.20 3 ;4 ;5 129.7 159 5.6 4 ;4@ 7.00 3 ;4 ;5 128.6 159 4.4 4 ;4@3@,5@ 7.26 128.5 1@ 7.34 128.6 160 1@ 7.22 128.0 160 1@4@ 7.22 126.8 2@,6@ 7.29 127.2 162 2@ ;6@ 7.15 126.2 162 2@ ;6@J(1,2) 9.6 4.2 4.1J(2,3) 4.3 D 0 2.5J(3,4) 8.5 12.0 1.3J(1,3) 2.1

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Surprisingly, the 1H spectrum of the isomeric 4exhibits three unresolved singlet signals with intensities1H, 2H, 1H for the protons of the partly saturated ring.According to the HMQC spectrum, the singlet at 3.96(2H) correlates with two di†erent carbon atoms. Theirextremely high values of 1J(C,H) couplings11 (181 and183 Hz, respectively) verify that they are included in theepoxide moiety (see Fig. 2).

Neither addition of benzene nor addition of shiftreagents was e†ective in resolving the virtual isochronyof H-1 and H-2 signals. Ultimately we managed toachieve this by dilution and we could measure the J(H,H) coupling constants. The small value of J(H-3,H-4)\ 1.3 Hz gives strong evidence for the trans-diaxialposition of the phenyl and ester groups. As a conse-quence of the axial orientation of the 4-phenyl group, adownÐeld shift of H-5 (7.11) and shielding of H-2@,6@(7.00) signals were experienced. The decreased value ofJ(C-2@,6@,H-4)\ 4.4 Hz indicates an increase in the pro-portion of the rotamer where the dihedral anglebetween the phenyl ring and the C-4ÈC-4a bond isnearly 0¡. The 3,4-diaxial conformer can be preferredonly in isomer 4, where the axially positioned ester doesnot exhibit any strong steric interactions with eitheroxirane or 4-phenyl moieties.

CD spectroscopy

We have recently reported the determination of theabsolute conÐguration of the main product, (])-3, andthe residual 1,2-dihydronaphthalene enantiomer, ([)-2,

by quantum chemical calculations of their CD spectraand comparison with the experimental spectra.4 Thisefficient method12h17 was also used to elucidate theabsolute stereostructure of the side product ([)-4,which, given its known constitution and relative con-Ðguration, should be represented by structure 4 (1S,2R,3S,4R) or the enantiomer 5 (1R,2S,3R,4S). For the calcu-lation of the chiroptical properties of ([)-4, a com-prehensive conformational analysis with semi-empiricalmethods was necessary to determine all the relevantconformers.

Starting with the arbitrarily chosen 1S,2R,3S,4R-enantiomer 4, the calculations gave rise to the detectionof seven minimum structures, which di†er in the follow-ing three conformational parameters (see also Table 2) :(a) the rotation of the ester O-methyl group about theneighboring CÈO bond (rotation about the dihedralangle a \ [ABCD] (see Fig. 3) ; (b) the rotation of the

Table 2. Characteristic structural and energetic data forall calculated conformers of 4

**Hf Position of PhaConformer (kcal mol~1) a (¡) b (¡) and CO2Me

4conf1 40.00 179.3 96.3 Equatorial4conf2 0.13 0.4 130.7 Axial4conf3 0.68 358.9 241.7 Equatorial4conf4 0.86 0.9 355.2 Axial4conf5 5.15 179.3 96.3 Equatorial4conf6 6.65 171.8 99.3 Axial4conf7 8.93 195.5 240.5 Equatorial

a For the 1-substituent (phenyl) rather pseudo-equatorial/pseudo-axial.

Figure 2. Gs-HMQC spectrum of 3 : (a) aromatic region; (b) alicyclic region; (c) alicyclic region with 1J(C,H) couplings.


CONFORMATION AND CONFIGURATION OF TETRALIN DERIVATIVE 57

Figure 3. Deünition of the dihedral angles a \ [ABCD],b \ [DCEF] and c\ [GHIJ].

carbonyl oxygen about the adjacent CÈC bond(rotation about the dihedral angle b \ [DCEF]; and (c)the conformational Ñexibility of the cyclohexene ring[axial or equatorial position of the phenyl (Phe) andester groups (E) ; see Scheme 2]. For the importanceof the dihedral angle c\ [GHIJ], see the discussionbelow.

For each of these seven conformational species,the individual single CD spectra were cal-4conf1È4conf7 ,

culated and then added up according to Boltzmann sta-tistics, i.e. according to their relative heats of formation,to give the calculated overall spectrum for 4. By reÑec-tion of this calculated (and subsequently “UV-correctedÏ12) spectrum at the zero line, the theoreticalspectrum for its 1R,2S,3R,4S-enantiomer 5 was obtainedin a rational way. Unexpectedly, neither of these twotheoretical spectra showed convincing agreement withthe experimental spectrum (see Fig. 4), so that, in con-trast to the main reaction product, (])-3, and theremaining starting material, ([)-2, an unambiguousattribution was not possible with sufficient conÐdence.

Since both epoxides, (])-3 and ([)-4, have the sametypes of chromophores, the reason for this failureshould be the apparent incapability of the AM1 calcu-lations to localize the correct minimum structures and

Figure 4. Comparison of the ‘UV-corrected’ calculatedCD spectra of 3 with the experimental spectrum.

to give their correct energies and thus weighting factorsfor the Boltzmann averaging. For this reason, we uti-lized the results of the conformational analysis obtainedby our NMR measurements for the CD calculations. Itwas found that in 4 the diaxial arrangement of substit-uents at C-3 and C-4 is energetically preferred (seeabove). This is in contradiction to the results of thesemi-empirical calculations, which favor a bis-equatorial array (see Table 2). Another signiÐcant di†er-ence between the AM1 results and the 1H NMRstructure is the prevailing position of the phenyl substit-uent with respect to the rotational angle c, on which, asthe calculations reveal, the CD behavior is stronglydependent. This angle had been calculated to be about50¡ (Fig. 5, left), but was found to be ca. 0¡ according tothe NMR and x-ray18 measurements (Fig. 5, right) (seelater).

For the CD calculations, the NMR-derived dihedralangle c was therefore incorporated into the lowestenergy bis-axial conformer, As the experimen-4conf2 .tally deduced dihedral angle of c\ 0¡ has to be con-sidered as a average of related possible conformationsof this Ñexible molecule, not only this particular confor-mation with c\ 0¡ was taken into consideration for theoverall theoretical CD spectrum, but a whole series of

Figure 5. Comparison of the 3D structure of i.e. the calculated lowest energy conformer that has the substit-4conf2

,uents R1 and R2 in axial positions (left ; c\ 53¡), and minimum structure in solution as proposed by the NMR measure-ments (right; cB 0¡).



related conformational species with all possible dihedralangles c\ 50¡ to [50¡, in steps of 10¡, with all theother parameters released for optimization. Owing tothe failure of the quantum chemical calculations inreproducing the experimentally determined structures,the heats of formation calculated for these species werenot considered reliable enough for the usual12 Boltz-mann weighting, suggesting just equally averaging thesingle CD spectra for the individual optimized struc-tures thus obtained. Figure 6 (left) shows the very goodagreement of the CD spectrum calculated for the 1S,2R,3S,4R-enantiomer 4 with the experimental spectrum,whereas the spectrum thus calculated for the 1R,2S,3R,4S-enantiomer 5 is virtually the opposite. This nowallows an unambiguous attribution a 1S,2R,3S,4R con-Ðguration to the absolute stereostructure of ([)-4.

The eventual clear and unambiguous outcome of theCD calculations again underlines the value and effi-ciency of this method for the elucidation of the absoluteconÐguration of chiral compounds. The transient prob-lems in this particular case were due to the incapabilityof the AM1 conformational analyses [including othersemiempirical and even ab initio calculations : for a pos-sible calculatory rationalization of this experimentallyfound conformational behavior of 4, further state-of-the-art quantum chemical calculation methods wereapplied to this molecule, among them the semiempiricalPM3 method and some ab initio methods (RHF/6È31G*//RHF/6È31G* and B3LYP/6È311 ] G*//B3LYP/6È311 ] G*). In all cases, however, the dihedralangles c for any of the conformers with diaxial positionsof both substituents (Ph and di†er signiÐcantlyCO2Me)from 0¡ (typically around 50¡). The reason for this con-formational behavior as deduced from the NMR mea-surements and, ultimately, conÐrmed by the good

Figure 6. Attribution of the absolute conüguration ofthe side product ([)-4.

agreement of the NMR-based CD calculations with theexperimental CD spectra, is still unknown]. To Ðnd thecorrect conformers to be used for the CD calculations,so that these minimum structures had to be determinedexperimentally, by detailed NMR investigations [morerecently, the NMR-deduced rotational position of thephenyl ring (cB 0¡) and the cyclohexene conformationwith (pseudo)axial position of the phenyl and estergroups were also found in the crystal, by an x-ray struc-ture analysis18].

COMPUTATIONS

Conformational analyses

Conformational analyses were carried out on SiliconGraphics IRIS 4D and INDIGO (R4000) workstationsusing the AM119 and PM320 methods as implementedin the program package VAMP6.1.21 The startinggeometries were pre-optimized by the TRIPOS22 forceÐeld.

CD calculations

For calculations of the rotational strength of electrictransitions from the ground state to excited states,the wavefunctions were obtained by CNDO/S-CIcalculations23 using a CI expansion including 576 singlyoccupied conÐgurations and the ground-state determi-nant. The rotational strengths were calculated by theuse of the BDZDO/MCDSPD24 program package. Allsingle CD spectra were then added up according toBoltzmann statistics, i.e. to their heats of formation,resulting in the theoretical overall CD spectrum, whichwas then submitted to a “UV correction.Ï12 For a betteroptical comparison with the experimental spectrum, therotational strengths were transformed into *e valuesand superimposed with a Gaussian bandshape function.

EXPERIMENTAL

Syntheses

Synthesis of compounds 2È4 have been published pre-viously.2a,4

Spectra

NMR spectra were measured on a Bruker DRX-500spectrometer at room temperature in ChemicalCDCl3 .shifts (ppm) are given on the d scale ; 1H NMR spectrawere referenced to internal TMS and 13C NMR spectrato the solvent ppm). In the 1D mea-(dCDCl3\ 77.0surements, 64K data points were accumulated.


CONFORMATION AND CONFIGURATION OF TETRALIN DERIVATIVE 59

500/125 MHz gradient-selected HMQC5

spectra. Relaxation delay s, evolution delayD1\ 1.5ms, 90¡ pulse 10.0 ls for 1H, 12.5 ls for 13CD2\ 3.45

hard pulses and 65.0 ls 13C GARP decoupling, 1Kpoints in sweep width 10 ppm in and 160 ppm int2 , F2

256 experiments in linear prediction to 512 andF1, t1,zero Ðlling up to 1K real points in apodization withF1,a n/2-shifted squared sine-bell in both dimensions.

500/125 MHz gradient-selected HMBC6

spectra. Relaxation delay s, delay for evolu-D1\ 1.5tion of long-range coupling ms (J \ 7 Hz),D6\ 70evolution delay ms, 80¡ pulse 10.0 ls for 1H,D2\ 3.4512.5 ls for 13C hard pulses, 1K points in sweept2 ,width 10 ppm in and 180 ppm in 256 experi-F2 F1,ments in linear prediction to 512 and zero Ðlling upt1,to 1K real points in and apodization with a n/2-F1shifted squared sine bell in both dimensions.

500/125 MHz phase-sensitive NOESY7

spectra. Relaxation delay s, mixing time 500D1\ 1.5ms, 90¡ pulse 10.0 ls, sweep width 10 ppm in andF1

2K points in 256 experiments in quadratureF2 , t2 , t1,detection in TPPI in linear prediction to 512 andt2 , t1,zero Ðlling up to 1K real points in apodization withF1,a n/2-shifted squared sine-bell in both dimensions. Toremove oxygen, we treated the samples in an ultrasonicbath.

2D semi-selective INEPT8 spectra. Relaxation delays, delay for evolution of long range couplingD1\ 1.5ms (J \ 7.5 Hz), evolution delay ms,D2\ 23 D3\ 28

90¡ pulse 10.0 ls for 1H, 12.5 ls for 13C hard pulses, 2Kpoints in sweep width 16 Hz in and 150 ppm int2 , F1

32 experiments in linear prediction to 128 realF1, t1,points in apodization with a n/2-shifted squaredF1,sine-bell in and sine-bell inF1 F2 .

Circular dichroism spectra. CD spectra were mea-sured on a Dichrograph CD 6 spectrometer (JobinYvon) at room temperature in hexane.

Acknowledgements

This project was supported by the Deutsche Forschungsgemeinschaft(Heisenberg Fellowship for T. L., Li 556/2-2, and the SFB 347 “Selek-tive Reaktionen Metall-aktivierter Moleku� leÏ), Hungarian ScientiÐcResearch Fund (OTKA, No. T026264) and by the Fonds der Chemis-chen Industrie. We thank Professor J. Fleischhauer (Universita� tAachen) and J. W. Downing (University of Colorado) for providing

the program package BDZDO/MCDSPD and K.-P. Gulden forporting it to LinuX.

REFERENCES

1. (a) B. F. Issell, F. M. Muggia, S. K. Carter, D. Schaefer and J.Schurig, Etoposide [V P-16] : Current Status and New Develop-ments. Academic Press, Orlando, FL (1984) ; (b) D. C. Ayres andJ. D. Loike, L ignans, Chemical, Biological and Clinical Properties,p. 85. Cambridge University Press, Cambridge (1990).

2. (a) T. Linker, K. Peters, E.-M. Peters and F. Rebien, Angew.Chem., Int. Ed. Engl. 35, 2487 (1996) ; (b) T. Linker, M. Maurerand F. Rebien, T etrahedron L ett. 37, 8363 (1996) ; (c) T. Linker, F.Rebien and G. To� th, J. Chem. Soc., Chem. Commun. 2585 (1996) ;(d) G. To� th, T. Linker and F. Rebien, Magn. Reson. Chem. 35, 367(1997).

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8. T. Jippo, O. Kamo and K. Nagayama, J. Magn. Reson. 66, 344(1986).

9. G. To� th, L. Hazai, Gy. Dea� k, H. Duddeck, H. Ku� hne and M.Hricovini, T etrahedron 44, 6861 (1988).

10. (a) G. To� th, A� . Szo� lloü sy, A. Le� vai, Gy. Oszbach, W. Dietrich andH. Ku� hne, Magn. Reson. Chem. 29, 801 (1991) ; (b) G. To� th, A.Le� vai and H. Duddeck, Magn. Reson. Chem. 30, 235 (1992) ; (c) G.To� th, A. Le� vai, A� . Szo� lloü sy and H. Duddeck, T etrahedron 49, 863(1993).

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12. For a recent review, see G. Bringmann and S. Busemann, NaturalProduct Analysis, p. 195. Vieweg, Braunschweig (1998).

13. J. Fleischhauer, A. Koslowski, B. Kramer, E. Zobel, G. Bring-mann, K.-P. Gulden, T. Ortmann and B. Peter, Z. Naturforsch.,T eil B 48, 140 (1993).

14. G. Bringmann, K.-P. Gulden, H. Busse, J. Fleischhauer, B.Kramer and E. Zobel, T etrahedron 49, 3305 (1993).

15. G. Bringmann, M. Stahl and K.-P. Gulden, T etrahedron 53, 2817(1997).

16. G. Bringmann, C. Gu� nther, S. Busemann, M. Scha� †er, J. D. Olo-wokudejo and B. Alo, Phytochemistry 47, 37 (1998).

17. G. Bringmann, S. Busemann, K. Krohn and K. Beckmann, T etra-hedron 53, 1655 (1997).

18. K. Peters E.-M. Peters, T. Linker and F. Rebien, unpublishedresults.

19. M. J. S. Dewar, E. G. Zoebisch, E. Healy and J. J. P. Steward, J.Am. Chem. Soc. 107, 3902 (1985).

20. J. P. Steward, J. Comput. Chem. 10, 209 (1989).21. G. Rauhut, J. Chandrasekhar, A. Alex, B. Beck, W. Sauer and T.

Clark, V AMP 6.1. Oxford Molecular, Oxford.22 SY BY L . Tripos Associates, St Louis, MO 63144.23. J. Del Bene and H. H. Ja†e� , J. Chem. Phys. 48, 1807 (1968).24. J. W. Downing, Program Packet BDZDO/MCDSPD. Department

of Chemistry and Biochemistry, University of Colorado, Boulder,CO; modiÐed by J. Fleischhauer, W. Schleker and B. Kramer ;ported to LinuX by K.-P. Gulden.


Documents

Elucidation of the conformations and absolute configurations of enantiomerically pure tetralin derivatives