A13C and1H NMR study of diastereomeric α-methylidene-β-hydroxy-γ-alkoxy esters

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  A13C and1H NMR study of diastereomeric α-methylidene-β-hydroxy-γ-alkoxy esters
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  A ' C and 'H NMR Study of Diastereomeric a-Methylidene+-Hydroxy-y=Alkoxy Esters Luca Banfi,* Donatella Potenza zyxwv nd Giuliana Severini Ricca zyxwv stituto di Chimica Organica dell'Universit8 and Centro CNR delle Sostanze Organiche Naturali, via Venezian 21 20133 Milano, Italy The ' C and 'H NMR spectra of ar-methylidene-P-hydroxy-y-alkoxy-pentan zyx nd -decanoates are presented. These data are consistent with a preferred conformation in which an intramolemlar hydrogen bond is present. Very characteristic steric zyxwvu hifts in the -C and 'H NMR pectra provide an eMent tool for the configurational assignment for this cl ss of compounds. INTRODUCTION During the course of our synthetic efforts towards the antibiotic conocandin (l), we studied the stereochem- CO,H 1 ical course of the base-catalysed condensation of 3- (dimethy1amino)propionates with chiral zyxwvut   -alkoxy- aldehydes to give, after methylation and elimination of the Mannich base, a diastereomeric mixture of zyxwvu nti and s n -a -met hylidene- - hy droxy - y -a1 koxy esters. (The terms anti and syn are used with Masamune et al.3 meaning:3 when the main chain is drawn in a zig-zag fashion, the syn isomer is that in which the two substituents project either towards, or away from, the viewer.) Consequently, we needed a method to assign the correct relative configuration to each diastereoisomer. Although 13C NMR spectroscopy has proved to be an excellent tool in the structural analysis of cyclic dias- tereoisomers, only a few, though significant, examples are known to its application to acyclic systems. ' We have found very clear 13C steric shifts that seem to be regular over the whole series of studied com- pounds, and that allow their easy analysis. RESULTS zyxwvut ND DISCUSSION The most characteristic 13C shifts of pentanoates 2-9 are listed in Table 1, and those for compounds 10-15 are shown in Table 2. The assignment of the C-3 and C-4 signals in 2-9 was accomplished by the 'H single-frequency selective decoupling technique (SFSD). Thus, by irradiating at the H-4 frequency, the broad doublet from C-4 col- lapsed into a broad singlet; the same effect was shown * Author to whom correspondence should be addressed. 6H OH z : R = PhCH,; R2 = Me 4: R'=PhCHz; R2= t-Bu 6: R'=CH,; R2=Me 8: R' = CH,O(CH,),; Rz = Me 3: R' = PhCH,; RZ = Me z : R' = PhCH,; R2 = t-Bu 7: R' = CH,; R2 = Me 9: R' = CH,0(CH2),; R2 = Me RO-0 , OH 10: R' = PhCH,; R2 = t-Bu 12: R' = CH3; R2=Me 14: R'=CH,; RZ=t-Bu OH 11 R' = PhCH,; R2 = t-Bu 13 R'=CH,; R2=Me 15: R' = CH,; R2 = t-Bu by the doublet corresponding to C 3 on irradiating at the H-3 frequency. As observed in 2-15, the signals of C-2, C-3, C-4 and C-5 of the anti isomers are always shifted upfield compared with the same carbons of the syn isomer. The most sensitive differences are those for C-5 (2.8- 3.4 Appm) and C-2 (1.3-1.9 Appm). This behaviour can be explained by assuming that the preferred con- formation is that which permits an intramolecular hydrogen bond between the hydroxy group and the alkoxy group (see Fig. 1 . This assumption is in agree- ment with previous The anti isomer is thus more sterically congested and, consequently, the C-2 and C-5 carbon signals are shifted upfield. The higher steric compression is probably also responsible for the upfield shift of C-3 and C-4. In contrast, the C-2' carbons are always shifted downfield in the anti isomer. On assuming a preferred conformation in which the hydrogen bond acceptor is CCC-0030-4921/84/0022-0224$02.00 224 ORGANIC MAGNETIC RESONANCE, VOL 22, NO. 4, 1984 zyxwvut   iley Heyden Ltd, 1984   C zyxwvutsrqp ND 'H NMR. zyxwvus IASTEREOMERIC zyxwv -METHYLIDEh E-0-HYDROXY-y-ALKOXY STERS Table 1 Wected -C NMR shifts (lippm) of diastereomeric a-methylidene-P-hydroxy-y-alkoxypentanoates in CDCI,' zyx  3 4 5 6 7 zyxwv   9 Carbon anti wn anti zyxwvuts Yn anti SYn anti sv 2 139.3 140.6 140.5 142.0 139.0 140.6 139.2 140.6 (+1.3) (+1.5) (+1.6) (+1.4) 2' 126.7 126.4 125.7 125.5 126.7 126.5 126.5 126.5 (-0.3) (-0.2) (-0.2) (0) 3 72.8 73.8 73.1 74.3 72.9 74.2 72.3 74.1 (+1.0) (+1.2) (+1.3) (+1.8) 4 74.6 75.9 74.9 76.6 74.7 76.5 75.5 76.5 (+1.3) (+1.7) (+1.8) (+1 O 5 13.8 17.1 14.1 17.3 13.9 17.3 13.8 17.2 1+3.3) (+3.2) (+3.4) (+3.4) OCH,O 93.0 93.6 93.1 93.8 95.2 95.9 94.3 94.7 (+0.6) (+0.7) (+0.7) (+0.4) zyx   A Ssvn anti) in parentheses. Table 2. selected =C NMR shifts (S ppm) of diastereomeric a-methylidene-P-hy&o~-y~o~d~oates n cDcl3'. 10 11 12 13 14 15 Carbon anti SYn anti wn anti wn 2 140.5 142.4 139.1 141.0 140.7 142.6 125.6 125.1 126.7 126.1 125.6 125.1 3 72.2 72.3 72.1 72.1 72.2 72.2 4 80.0 81.0 80.2 80.9 79.9 81.2 (+1.0) (+0.7) (+1.3) 5 28.9 31.7 28.9 31.8 28.9 31.8 (+2.8) (+2.9) (+2.9) OCH20 94.1 94.8 96.4 96.9 96.2 96.9 +0.7) (+0.5) (+0.7) a A 8- -aanr,) n parentheses. (+1.9) (+1.9) (+1.9) (-0.5) (-0.6) (-0.5) (+0.1) (0) (0) Table 3. Wected =C NMR shaQ (6 ppm) of diastereomeric ar-methylidene-P-hy~o~-y-alkoxy esters in Meow 4 5 6 7 14 15 Carbon anti sw anti sw anti SYn 2 144.5 144.5 142.9 143.1 144.3 144.6 (0) (+0.2) (+0.3) 2 124.9 125.4 126.1 126.5 125.0 125.2 3 73.0 74.0 73.3 74.0 71.9 72.1 4 76.2 76.5 76.2 76.2 80.3 80.3 5 14.7 17.2 14.8 17.1 30.2 32.4 OCH,O 93.7 94.5 96.1 96.7 96.6 97.5 a A (Ssvn Senti in parentheses. (+0.5) (+0.4) (+0.2) +1 .O (+0.7) (+0.2) (+0.3) (0) (0) (+2.5) (+2.3) (+2.2) (+0.8) (+0.6) (+0.9) one of the carbonyl oxygens (six-membered rings), it is more difiicult to rationalize the spectroscopic data, particularly the large shift differences for C-5 and C-2, and the vicinal coupling constants between H-3 and H-4 (see below). Another proof of the existence of this intramolecu- lar hydrogen bond is given by the IR spectra (CCl,) of these compounds, which show a non-polymeric 0-H stretching band at 3580-3590 cm-', and independent of concentration. In the 'H NMR spectra (200 zyxwvu Hz , moreover, the OH proton appears in every case as a doublet with a coupling constant of 4.5 Hz, which is typical of an intramolecularly hydrogen-bonded OH group. 13C shifts in MeOD (Table 3) give other useful information: the difference between the C-2 shifts of anti and syn compounds is near to zero, while this difference is also decreased for C-5 and C-4, although syn nti Figure 1. Proposed preferred conformation for 2-15 in CDCI . to a lesser extent. Moreover, the C-2' carbons of anti diastereoisomers, which resonate from the syn dias- tereoisomers downfield in CDCI,, are now shifted upfield. These effects are probably due to the forma- tion of intermolecular hydrogen bonds with the sol- vent. Another interesting feature is the variation of the C-3 shifts on going from the pentanoate to the de- canoate series, where syn compounds undergo an upfield shift of approximately 2ppm because of the y effect'' provoked by C-6 (see Fig. 2). In contrast, the anti compounds are shifted by only 0.8-0.9ppm, and Dreiding models show very clearly that this y effect is no longer possible. Table shows selected data from the 'H Nh4R spectra of compounds 2-15. The vicinal coupling con- stants between H-3 and H-4 cannot be used for anti syn Figure 2. yEffect between C-6 nd C-3 in 1 15. ORGANIC MAGNETIC RESONANCE, VOL. 22, NO. 4, 1984 225  L. BANFI, D. zyxwvut OTENZA AND G. SEVERINI RICCA Table 4. Selected 'H NMR zyxwvut ata m CDCl, for eompoundis. 2-15 zyxwvutsr   zyxwvutsrqponml -3 S Hab S H-5' J(H-3, Ha) (Wd Compound Configuration (ppm) (ppm) (pprn) 2 anti 4.64 4.05 1.11 4.0 4 anti 4.58 4.06 1.12 4.2 5 SYn 4.37 3.91 1.22 4.8 6 anti 4.70 3.98 1.10 4.0 7 SYn 4.43 3.83 1.21 4.2 8 anti 4.68 3.95 1.03 3.6 9 SYn 4.35 3.84 1.14 5.0 10 anti 4.63 3.87 7.5 11 SYn 4.45 3.74 4.2 12 anti 4.60 3.76 7 O 13 SYn 4.42 3.65 7 O 14 anti 4.61 3.78 7.0 15 SYn 4.44 3.69 7 .O Doublet of quartets for 2-9 and doublet of triplets for 10-15. Doublet for 2-9. Determined by examination of the H-4 peaks and also with Not assigned. 3 SYn 4.41 3.94 1.22 4.7 a Multiplet. the aid of double resonance experiments. stereochemical assignment as their values are too close. However, it is worth noting that these values are in agreement with the preferential conformation pro- posed. The 'H chemical shifts of the methyl groups in pentanoates 2-9 show a regular upfield shift of zyxwvu a 0.10ppm between the anti and svn isomers. Even in this case this can be attributed to steric compression of the methyl group in the anti compounds' (see Fig. 1). The configuration of esters 2-15 has been further proved by transformation' of decanoates 14 and 15 into the epoxides 16 and 17. The vicinal coupling zyxwv T 16 ~ ~ Table 5. Selected 13C NMR shifts (6 pm) of diastereomeric or-methytidene-B,y-epoxydecanoates n CDCl; Compound Configuration C-2 12-2' C-3 C-4 C-5 16 trans 139.1 122.9 62.8 55.2 32.2 17 cis 136.3 125.7 59.0 55.4 26.4 (1-2.8) (-2.8) (1-3.8) (-0.2) (+5.8) a A -a,,, in parentheses. for cis trans assignment of epoxides.' Since our synth- esis involved a stereospecific inversion at C-4,' 14 must be anti and 15 must be syn. Table 5 shows selected I3C shifts of these epoxides. For the same reasons described above (higher steric compression), the signals of C-2, C-3 and C-5 are shifted upfield in the cis with respect to the trans epoxide . EXPERIMENTAL 13C NMR spectra were recorded at 25 C on a Varian XL-100 FT spectrometer at 25.2 MHz with heteronu- clear lock. Solutions of 0.5-1.0~ were used (5mm tubes). In the case of the MeOD spectra, the higher dilution (0.1 M) did not affect the chemical shifts. The two compounds of every pair of diastereoisom- ers were always recorded at the same concentration. The data acquisition conditions of the free induction decay were pulse width 10 zy s, acquisition time 0.8s (with a spectral width of 5000 zy z nd a pulse delay of 0.5 s. 'H noise decoupled pulse operation (Fourier) was used. 'H single-frequency off -resonance decoup- ling (SFORD) and 'H single-frequency selective de- coupling (SFSD) techniques were also used as assign- ment aids. The chemical shifts are in ppm 8) from internal TMS, and the accuracy of the spectral line positions is *0.05 ppm. 'H NMR spectra were recorded at 25°C on a Varian XL-200 FT spectrometer at 200 MHz with heteronuclear lock; 0.2 M solutions were used (5 rnm tubes). The data acquisition conditions of the free induction decay were pulse width 5 ~s and an acquisi- tion time of 4 s (with a spectral width of 2000 Hz). he chemical shifts are in ppm (6) from internal TMS and the accuracy of the spectral line positions is ~t0.005 pm. Acknowledgements We thank Mr R. Arosio for his collaboration in this work and MI S. Crippa for technical assistance. This research was assisted financially bv a erant from the Proeetto Finalizzato Chimica Fine e Secondaria 'Onstant between H-3 and H-4 shows that l 5(34) 2.1 ] is trans while 17 J(34) = 4.6 fi] s Cis. Proton vicinal coupling constants have been previously used del 6N.R. REFERENCES 1. J. M. Miiller, H. Fuhrer, J. Gruner and W. Vaser, Hefv. Chim. Angew. Chem., Int. Ed. Engl. 557 (1980). 2. L. Banfi, L. Colombo C. Gennari and C. Scolastico, J. 133 (1981), and references cited therein. 3. S. Masamune, A. Sk. Ah, D. L. Snitman and D. S. Garvey, Acta 59, 2506 (1976). Chem. Soc., Chem. Commun. 1112 (1983). 4. H.-J. Schneider and M. Lonsdorfer, Org. Magn. Reson. 16, 5. C. H. Heathcock, M. C. Pirrung and J. E. Sohn, J. Org. Chem. 44, 4294 (19791, and references cited therein. 226 ORGANIC MAGNETIC RESONANCE, VOL. 22, NO. 4, 1984  I3C zyxwvutsr ND H zyxwvut MR. IASTEREOMERIC zyxwvu -METHYLIDENE-f3-HYDROXY-y-ALKOXY zy STERS 6. zyxwvutsrq . Kuhns and H. Rembold, zyxwvuts rg. Magn. Reson. zyxwvut 6, 138 (1 981 . 7. J. Uzawa, S. Zushi, Y. Kodama, Y. Fukuda, K. Nishihata, K. Urnemura, M. Nishio and M. Hirota, Bull. Chem. SOC. pn. 53, 3623 (1980). 8. G. C. Levy. T. Pehk and E. Lippmaa, Org. Magn. Reson. 14, 214 (1980). 9. M. ul Hasan, Org. Magn. Reson. 14, 309 (1980). NMR Spectra, p. 28. Heyden, London (1980). 10. F. W. Wehrli and T. Wirthlin, hterpretation of Carbon-ld Received 21 June 1983; accepted (revised) 3 September 1983 ORGANIC MAGNETIC RESONANCE, VOL. 22, NO. 4, 1984 227
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