MAGNETIC RESONANCE IN CHEMISTRY, VOL. 24, 681-686 (1986)

Stereochemical Investigations on (E)-homoeburnane Derivatives by 'H and 13C NMR Spectroscopy?

Gabor T6th* and Csaba Szantay Jr.$ Department of General and Analytical Chemistry, Technical University, Gellert t6r 4, H-1111 Budapest, Hungary

Zsuzsa Kardos, Maria Incze, Ferenc S6ti and Csaba Szantay Central Research Institute for Chemistry, Hungarian Academy of Sciences, Pusztaszeri ut 59/67, H-1025 Budapest, Hungary

George Kotovych Department of Chemistry, University of Alberta, Edmonton, Alberta, T6G 2G2, Canada

Several 14-hydroxy-14a-methyl-(E)-homoeburnane diastereoisomers have been synthesized and studied by 'H and "C NMR spectroscopy. 1D NOE difference experiments, together with proton-proton correlation and decoupling measurements, have allowed the complete assignment of the 'H and 13C NMR spectra. The relative configurations and predominant conformations have been established.

KEY WORDS Stereochemistry, conformational analysis, 'H and 13C NMR, E-homoeburnane, NOE difference spectroscopy

INTRODUCTION

The remarkable biolo ical activity of alkaloids with the eburnane skeleton has drawn attention not only to the synthesis of these natural products, but also to the preparation and stereochemical investigation of potentially active, non-natural (E)-homoeburnane derivatives.2 In order to study structure-activity relationships, 14a-substituted derivatives containing a hydroxy function in position 14 have been synthes- ized, and the stereochemistry of these compounds studied by NMR methods. We have recently reported the 13C and 'H NMR study of 14a-unsubstituted 14-hydroxy-(E)-homoeburnane e p i m e r ~ . ~ This work can be regarded as an extension of the above investigation to a more complicated model having an additional centre of chirality.

K

SYNTHESIS

Lactam l4 was methylated by methyl iodide in liquid NH3 in the presence of NaNH2 (Scheme 1); only one epimer (2) was formed. On boiling epimer 2 in benzene in the presence of KOBu', a small amount of its stereoisomer 3 was isolated. The thermodynami- cally favoured main product 2 was reduced with

* Author to whom correspondence should be addressed. t Synthesis of Vinca Alkaloids and Related Compounds, Part 19. For Part 18, see Ref. 2. *On leave from the Chemical Works of Richter Gedeon Ltd., H-1475 Budapest, Hungary.

0749-1S81/86/080681-06$05 .OO 0 1986 by John Wiley & Sons, Ltd.

R OH R

4 d p M e 5 p P M e r u @Me

Q P - 8 d -

Scheme 1.

2, l 4 a - M e p 3, l 4 a - M e d

6

LiAlH4. Owing to possible enolization, four amino- carbinols (I-IV, Scheme 2) can theoretically be formed as a result of the above treatment, but only 4 and 5 were actually isolated. The further-reduced alcohol 6 was also obtained as a by-product. Reduction of the minor product 3 under the same conditions yielded one new aminocarbinol, 7, accompanied by 4. The latter finding substantiates the above-mentioned possibility of enolization and,

Received 9 October 1985 Accepted 25 November 1985

682 G. TOTH ET AL.

R

n

n

IV.

no

i7

n

Unlabelled bonds denote H. Scheme 2.

consequently, epimerization in the course of the reduction. None of the structures of the three aminocarbinols obtained can therefore be assigned a priori, and thorough spectroscopic studies were needed in order to elucidate the steric position of the substituents.

RESULTS AND DISCUSSION

In a previous publication3 we reported that in 14a-unsubstituted 14-hydroxy-(E)-homoeburnanes two possible stable conformations of the seven- membered ring must be taken into account-a chair (8, b type) and a twist boat (9, a type) (see Scheme 2). This makes the determination of the stereochemistry of 4, 5 and 7 more complicated. In P-14a-Me isomers the chair conformation involves a 1,3-diaxial interac- tion between the methyl group and C-17 (Ib and IIb), and it is therefore expected that the twist boat will predominate in these diastereoisomers. In the 14a-unsubstituted compounds 8 and 9 we have observed that, in minimizing the 1,3-allylic strain5 with the indole ring, the 14-OH group tends to occupy a quasi-axial position, even if this brings the E ring into a twist boat conf~rmation.~ The 'H chemical shifts and characteristic coupling constants of 2, 4 and 5 are summarised in Tables 1 and 2. The 'H NMR spectra obtained at 400 MHz could be analysed as first order. Even at this high field, owing to the overlap of the multiplets neither standard decoupling nor 1D NOE

Table 1. 'H chemical shifts (ppm) for 2,4,5 and 7 Proton

Ha-3 He-5 Ha-5 He-6 Ha-6 H-9 H-10 H-11 H-12 H,-14 Hp-14 H,-14a Hp-14a Ha-1 5 Hp-15 He-17 Ha-17 He-18 Ha-18 He-19 Ha-19 H,-20 H,,-20 H3-21 14a-CH,

28

4.13 3.32 3.01 2.44 3.10 7.42 7.31 7.25 8.52 - -

2.77

1.84 1.57 1.48 0.97 1.37 1.68 2.63 2.73 2.06 1.69 0.93 1.30

-

4b

4.24 3.25 2.94 2.43 3.06 7.48 7.1 1 7.22 7.41

5.57 -

2.15d.e

1.60 1.44' 1 .43e 0.88 1.37 1.67 2.66 2.77 2.08drf 1.65'*' 0.89 1.28

-

Sb

4.1 1 3.29 3.02 2.51 3.10 7.57 7.15 7.22 7.47 5.62

2.30

1.57 1 .78d*e 1.44 1.27 1 .33e 1 .74e 2.59 2.78 1.96 1.74e.f 0.93 1.17

- -

a Measured at 250 MHz. Measured at 400 MHz. Measured at 360 MHz. From a 20 COSY45 experiment.

From a 1D NOE difference experiment, 'From a decoupling experiment.

7 c

3.96 3.19

2.41

7.40 7.05 7.13 7.30

5.87

2.27e 2.08 1.33 1.08 1.37 1.28 1.78 2.50 2.65 2.04 1.59 0.83 1.16

2.85-3.05

2.85-3.05

- -

difference measurements (Fig. 1 and Table 3) could be used to assign all the proton resonances. Complete assignment was possible by means of the two- dimensional proton-proton correlation map, and to obtain better resolution we used the COSY-45 version.6 This measurement allows the determination of the chemical shifts of the overlapping H,-15, H,-18 and H,-20 signals in the spectral range 1.4-1.7ppm for 4 and 1.7-1.8 ppm for 5.

The multiplets corresponding to H-3, H-14, H3-21 and l4a-Me were readily assigned on the basis of their characteristic chemical shifts. Irradiation of H-14 in 4 and 5 results in positive NOES to H-12 and H-14a and negative NOES to H-11, allowing the unambiguous assignment of these protons. The H2-5 and H2-6 methylene protons give well separated subspectra, and the Hz-6 protons exhibit large 5J long-range couplings with H-3. 'J,,,, is approximately 1 Hz larger than 'JCi,, which is in good agreement with the Barfield- Sternhell theory on the geometry dependence of homoallylic coupling constants.73s As found in other indole alkaloids, d(Ha-6) is larger than &(H,-6), owing to the anisotropic effect of the condensed aromatic ~ y s t e m . ~ ~ ' ~ The strong downfield shift of the Ha-19 signal in the C/D cis fused rings can be explained by the same effect. There is a characteristic difference between the '3(19a, 19e) (10.5-11.0 Hz) and 'J(5a, 5e) (12.0-12.9 Hz) values in 2 ,4 and 5. The decreased absolute value of 2J(19a, 19c) is due to an antiperi lanar effect of the nitrogen lone pair on H,-19.'p1z On the proton-proton correlation map of

'H AND I3C NMR OF E-HOMOEBURNANE 683

Table 2. Selected coupling constants (Hz) for Table 3. Results of proton-proton 1D NOE difference 2,4,5 and 7 experiments on 4 and 5

2J P 4b

5,5 12.0 12.9 6,6 16.0 16.0 15.15 14.8 14.5 17,17 14.5 15.0 18,18 13.0 13.2 19,19 11.0 10.5 20,20 15.0 15.0

12.0 4.5 5.0 0.5

8.4

3J d

d

d

d

5,.6, 5af6e 5e16a 5at6e 14,,14a, - - 14@,14a, - 14@,14aD - -

14a, ,15, - - 14aD ,1 SD - _.

14a,,15@ 10.5 8.7' 14a,, 15, 1.5 <l.Oe

17,,18, 12.5 -12.0 17,,18, 3.5 3.0 17,,18, -1.5 1.5 17,,18, -3 3.0 f8,,19, -12 11.8

18,,19, -3 3.0 18,,19, -3 3.0

3ag6a -3 2.8

' Measured at 250 MHz. Measured at 400 MHz.

" Measured at 360 MHz. Higher order sub-spectrum. From decoupling

18,,19, 4.5 3.5e

5J

3as6e 1.9

5b 7c

12.1 15.5 15.1 15.0 14.0 13.5 13.2 13.0 11.0 11.0 13.7 14.1

12.0 d 4.5 d 5.0 d 0.5 d 1.6

- <1.0 10.4 - 1.7 - - 12.2 - <1.0 12.0 13.0 4.1 4.3 3.0 4.3 3.0 -3

12.4 12.5 4.4e 4.3 3.6 3.7 3.0 -3

3.0 2.0

d

d

- - -

d

d

1.28

1 , 1 1 1 1 1 1 1 1 1 1 , 1 , 1 1 1 / 1 1 / ~ 1 1 1 / 1 1 1 1 1 t $ t L

Figure 1. 400MHz 'H NMR spectrum of 4 and the 'D NOE difference experiment on saturating H-14.

7 6 5 4 3 2 1

Irradiated Compound proton Proton observed, NOE(%)'

4 H,-14b H-12 (19.0%), H,-14a (2.1%), Me-14a (1.3%), HD-15 (2.4%)

H,,-20 (4.4%), Ha-21 (1.5%)

Ha-6 (6.0%). He-18 (5.0%), Ha-17 (3.0%)

H-3" Ha-5 (4.2%), H, - 14a + H,-20 (8% + 3%).

59 He-14b H-12 (15.9%), H,-14a (7.8%), Me-l4a (1.4%)

Ha-5 (4.2%), H, - 14a + H,-20 (8% + 3%). Ha-lgb H-3"

H,-14aC H-3 (8.7%). He-14 (8.5%) H,-20 (4.4%), HS-21 (1.5%)

aThe NOE (%) refers to 1H.

" Measured at 250 MHz. Measured at 400 MHz, degassed sample.

5, H-3 shows further long-range couplings to the zig-zag arranged H,-17 and to Hx-20.

Owing to the chiral structure the H2-20 methylene protons are diastereotopic. However, their large chemical shift differences [~lli(H,,~) = 0.43 in 4 and 0.22ppm in 51 indicate that the populations of the possible conformations around the C-16C-20 bond are very different.

In view of the conformational possibilities shown in Scheme 2 (the 'sticks' denoting the steric arrangement of the CH bonds), the configurations of 4 and 5 were determined by the following 'H NMR arguments. In 4 J(H-14, H-14a) = 8.4 Hz. Using the modified Karplus equation and also taking into account the electronega- tivity of the sub~tituents,'~ we calculated the corresponding dihedral angle to be cu 180". On the basis of this value only Ia and IVb can be considered as possible structures. A choice was feasible by 1D NOE difference measurements, as in these spectra the interproton distances are sensitively reflected by the resulting signals and their inten~ities.'~,'~ Saturation of the H-3 signal produced a NOE enhancement for H-l4a, showing that these protons are in close proximity and proving the structure to be Ia. Irradiation of HB-14 resulted in a strong enhancement for H-12. This NOE, i.e. the reduced H-12 and HB-14 distance, is indicative of a deformation of the flexible twist-boat J3 ring caused by the steric repulsion between 14-OH and H-12. Structure Ia for 4 was further supported by the measured NOE to HB-15 when irradiating H-14.

In 5 J(H-14, H-l4a)= 1.6Hz. On applying the modified Karplus equation, this value corresponds to a cu 60" dihedral angle, which can be achieved with structures IIa, IIb, IIIa, IIIb and IVa. On considering that J(H-l4a, H-15B) = 10.4 Hz, the possible struc- tures are reduced to IIa and IIIb. Saturation of H-3 resulted in an NOE (see Table 3) for Ha-14a, and vice versa, indicating the close proximity of these protons and proving the structure to be IIa. In accordance with the C/D c k ring fusion, an NOE was observed to Ha-6 on saturating H,-19.

The geometries of 4 and 5 are thus similar, differing only in the configuration at C-14. In 4, owing to the synclinal arrangement of 14-0H, a 0.15 ppm upfield shift was found for Ha-14a in comparison with the

684 G. TOTH ET AL.

antiperiplanarly arranged isomer 3. A high shielding was observed for Ha-17 in 4 and 2 as this proton is in the shielding zone of the indole system. A similar effect is expected for 5 , but here the OH group is close to Ha-17 and produces the observed small downfield shift. The Hp-15 signal in 5 is 0.34ppm downfield of its position in 4, which is also due to the 1,3-diaxial effect of the p-OH group.

13C NMR provided further evidence for the structures proposed above. We previously reported that in 14a-unsubstituted a- and P-14-OH epimers 8 and 9, the C-3 and C-17 chemical shifts were of diagnostic value in determining the conformation of ring E.3 In the twist-boat 9, owing to the strong y-syn interaction with C-l4a, C-3 is more shielded than in 8 , . which exists in a chair conf~rmation.~ In 8, however, the y-gauche steric effect between C-14a and (2-17 produces an upfield shift of C-17. It is expected that the introduction of a 14a-Me group would not alter the chemical shifts of C-3 and C-17 in the 6 position significantly, if the chair Ft twist-boat conformational equilibrium is not influenced. The chemical shifts of C-3 and C-17 (61.5 and 31.4ppm, respectively) in 4 therefore indicate the Ia stereochemistry. This conclusion, however, can only be based on the unambiguous assignment of C-17, which is near the C-20 signal (28.2 ppm). Selective 13C{ 'H} decoupling experiments proved the assignments given in Table 4. The chemical shifts of C-17 and C-3 in 5 show that the predominant conformation for ring E is the twist boat.

As expected, in 4, where the &-OH group is in the quasi-equatorial position, the C-14 signal is shifted significantly downfield from its value in epimer 5, which has a quasi-axial 14-OH. Both the y-gauche and y-anti effect of an OH group produce an upfidd shift,16 and 6(C-15) is therefore similar in 4 and 5.

Table 4. =C chemical shifts (ppm) for 2-5 and 7-9 Carbon

No.

2 3 5 6 7 8 9

10 11 12 13 14 14a 15 16 17 18 19 20 21 14a-CH3

2 3

133.1 133.1 62.4 65.3 51.5 51.9 17.7 17.7

117.5 118.3 129.9 129.3 117.5 117.6 123.5 123.1 124.7 124.8 117.5 116.3 136.3 137.2 175.6 176.5 34.7 36.5 42.1 41.4 37.7 38.2 32.6 26.9 21.3 21.2 45.9 45.8 29.1 30.8 7.8 7.5

17.4 19.4

4 5 7 88 98

134.6 133.8 134.8 134.7 134.2 61.5 62.1 63.8 64.0 62.2 51.9 52.2 51.6 51.6 52.4 17.4 17.6 17.5 17.4 17.4

111.6 110.2 111.3 111.3 110.6 129.5 128.0 128.0 128.1 128.3 118.3 117.9 118.0 118.0 117.9 120.2 120.2 119.9 119.8 120.3 121.8 122.0 121.5 121.6 122.1 110.5 110.7 109.1 109.3 110.9 137.6 137.5 136.6 136.5 137.9 86.0 83.4 80.6 76.5 79.7 32.8 32.1 32.6 30.7 32.9 38.9 37.9 38.2 28.3b 30.2b 39.8 38.3 38.7 38.8 38.9 31.4' 32.8 26.4 26.3 29.0b 21.1 21.5 21.0 20.9 21.7 46.2 45.4 44.3 44.5 45.7 28.2 30.7 31.0 29.4b 28.5 7.8 7.8 7.5 7.5 7.7

20.6 21.1 21.7 - - a Ref. 3.

' Assignmment confirmed by selective decoupling of the corresponding proton.

Tentative assignment.

The 13C NMR data also give valuable information on the conformational equilibrk of ring E in 2 and 3. It is seen from the value of 6(C-17) = 32.6 that in 2 the predominating conformation of ring E is the twist-boat. In the 'H NMR spectrum we found that J(H-l4a, H-15) = 10.5 Hz and this, together with the 13C analysis, proves the p configuration of 14a-Me. Thus, the p position of 14a-Me in 2, 4 and 5 is in accordance with that expected from configurational correlations.

The C-3 and C-17 signals indicate a chair conformation for the E ring in the a-14a-Me epimer 3. The y-gauche interaction between C-14a and C-17 causes a 5.7 pprn upfield shift of the C-17 signal.

In aminocarbinol 7, with an a-14a-Me configura- tion, the chemical shifts of C-3 and C-17 are 63.8 and 26.4, respectively, which are in good agreement with values measured in 3 and 8, and correspond to a chair conformation for ring E. This, and the <1 Hz value of J(H-14, H-14a) (ca 60" dihedral angle) (Table 2), allows the assignment of structure IIIb to compound 7. This geometry is further supported by the 12.2Hz coupling between H,-14a and a-Ha-15, and the 4J = 0.6 Hz coupling between Ha-14a and a-Ha-15, and the 4J = 0.6 Hz coupling between the zig-zag arranged He-14 and He-15. Ha-17 is deshielded in 7 compared with 4, reflecting the twist-boat + chair interconversion of ring E. This deshielding can be explained by the resulting y-gauche steric interaction between Ha-(2-17 and Hp-C-14a. '' The observed shielding of He-17 may be connected with the same conformational change. Analogous to the effect found on Hp-15 in 5, the 1,3-diaxial interaction of a-14-OH and H,-15 causes deshielding of H,-15.

EXPERIMENTAL

Spectroscopy

All the NMR spectra were recorded in the P I T mode, with internal deuterium lock at ambient temperature (298K), in CDC13 using TMS as internal standard. The 'H measurements were performed on Bruker WH-400/DS, Bruker WM-360, Bruker WM-250 or Jeol FX-100 spectrometers at 400, 360, 250 or 100 MHz, respectively. All 13C NMR experiments were carried out at 25MHz usin a Jeol FX-100 spectrometer, except for the '%{'H) selective decoupling experiment, which was performed on the Bruker WH-400/DS spectrometer at 100 MHz.

Carbon multiplicities were determined by the attached proton test (APT) methodi8 and by noise-modulated off-resonance decoupling (NORD)'' where necessary.

The 'H chemical shifts and coupling constants were calculated as first-order spectra at 400MHz, and are reported with an accuracy of approximately f 0.01 ppm and f0.20 Hz, respectively. The solutions used for the 400 MHz NOE difference experiments were degassed four times using the freeze-pump- thaw technique, and then sealed under vacuum. All glassware was cleaned extensively, including a nitric

'H AND 13C NMR OF E-HOMOEBURNANE 685

acid wash to diminish paramagnetic impurities. For NOE measurements a delay time of 8 s was used. The two-dimensional COSY 45 experiments were recorded at 400MHz, using the Bruker software package (2D spectral width 2000Hz, delay time 2.0s, number of repetitions 8, number of increments 512, J?T size 1K X 1K).

Synthesis

(+)-(3S 14aR : 16S)-l~-Methyl-(E)-homoeburnamenine- 14(14aH)-one (2). To stirred liquid ammonia (50- 60ml) a small piece of sodium metal was added at -60°C. After the appearance of a blue colour, a few crystals (about 0.1 g) of iron(II1) nitrate hydrate were added, followed by sodium (0.5 g; 0.0217 mol). After all the sodium had been converted into the amide and the deep-blue colour had disappeared, a solution of 1 (5 g, 0.0162 mol) in anhydrous tetrahydrofuran (50 ml) was added dropwise. The mixture was stirred for approximately 3 h while the temperature rose to -45"C, and a solution of methyl iodide (1.3m1, 0.021 mol) in anhydrous tetrahydrofuran (5 ml) was then added. After stirring for 15min, the ammonia was allowed to evaporate at room temperature. The mixture was concentrated under reduced pressure and the residue dissolved in CHCl, and washed with water. The organic phase was dried (MgS04) and evaporated. The crude product was crystallized from ethanol giving 2 (3.3g, 63.2%), m.p. 144-145"C, [a]DZ5 = +29" (c = 1.0, CHCl,). IR (KBr): 1705 cm-l (YCO). C&Hz6Nz0 (322.44): found, C 77.96, H 8.07, N 8.71%; calculated, C 78.22, H 8.13, N 8.69%.

(+)-(3S: 14aS: 16S)-14a-Methyl-(E)-homoeburnamenine- 14(14aH)-one (3). To a solution of lactam 2 (1 g, 0.0031 in mol) in anhydrous benzene, potassium tert. -butoxide (100 mg) was added in anhydrous benzene (20 ml) and the mixture was refluxed for 10 h. After cooling the solution was evaporated under reduced pressure and the residue was separated by column chromatography on silica gel with elution by light petroleum-ethyl acetate-diethylamine (lO:lO:O.l), giving 3 (36mg, 3.6%), m.p. 139-

1690 cm-' ( YCO). 141 "c , [g]DZ5 = +21" (C = 1.0, CHC13). IR (KBr):

(-)- (3S:lS: MaR:l&S)-l4a-Methyl-14,14a-dihydro- (E) - homoebumamenine-14-01 (4), (+)-(3S:14R:14aR:lW)-14a- methyl-l4,l4a-~ydro-(E)-homoebum~enine (5) and (-)- (1s: 12bS)-l-et~yl-l-[(S)-3-hydroxy-2-methylpropyl]-1,2,3,4, 6,7,12,12b-octahydroindolo[2,3-u]quinobine (6). Lith- ium aluminium hydride (1.5 g, 0.039 mol) was suspended in anhydrous tetrahydrofuran (100 ml) in an argon atmosphere. A solution of 2 (3.05g7 0.00946 mol) in anhydrous tetrahydrofuran (50 ml) was added dropwise at reflux temperature with stirring and the mixture was refluxed for a further 1.5 h. After cooling in an ice-bath the excess of lithium aluminium hydride was decomposed by adding 1.5ml of water, 1.5 ml of 15% sodium hydroxide solution and 6 ml of water successively. The precipitated solids were removed by filtration and washed with chloroform.

The filtrate and washings were combined, dried (MgS04) and concentrated under reduced pressure. The residue was separated by column chromatography on silica gel, with elution by 10% v/v ethanol- chloroform, separating 4 and 6 from 5, then by 20% v/v diethylamine-cyclohexane, separating 4 from 6.

Compound 4 was a white oil (320mg, 10.4%),

ethanol-chloroform), 0.56 (20% v/v diethylamine- cyclohexane). IR (CHCl,): 3595 cm-' (YOH). CzlHz8Nz0 (324.45): found, C 77.68, H 8.72, N 8.61%; calculated, C 77.73, H 8.70, N 8.64%.

Compound 5 was white crystals (l.Og, 32.6%),

RF = 0.38 (10% v/v ethanol-chloroform), 0.56 (20% v/v diethylamine-cyclohexane). IR (CHC13) : 3590 cm-' (YOH). G1H2*N20 (324.45): found, C 77.75, H 8.66, N 8.99% calculated, C 77.73, H 8.70, N 8.64%.

Compound 6 was white crystals (1.1 g, 35.6%), m.p. 193-196 "C, [aIDz5 = -7.4" (c = 1.0, CHCl,), RF = 0.62 (10% v/v ethanol-chloroform), 0.31 (20% v/v diethylamine-cyclohexane). IR (CHCl,): 3630 cm-' (YOH), 3495 em-' (YNH), 2810, 2760 cm-' (Bohlmann bands). &1H30N20 (326.47): found, C 76.88, H 9.13, N 8.70%; calculated, C 77.25, H 9.26, N 8.58%. 'H NMR (100MHz, 6): CH3(CHz) 1.14(3H, t), Me 0.90(3H, d), NCH 3.30(1H7 s), NH 7.95(1H, brs). 13C NMR: 6 CH3CHzC 8.2, 31.4, 40.3, HOCH2CH(Me)CHz 69.6, 30.8, 19.8, 36.2, p- carboline 66.9, 54.4, 21.7, 111.5, 126.9, 117.9, 119.4,

56.9.

[aD2' = -22.33" (C = 1.0, CHCl,), RF = 0.62 (10% V/V

m.p. 178-187 "c, [(Y]D~' = +104.8" (C = 1.0; CHCl,),

121.5, 110.8, 136.0, 133.8, CHZCHZCHZN 33.1, 22.2,

-(3SlAT:14aS: 16S)-l4a-Methyl-14,14a-d&ydro-(E)-homo- eburnamenine-14-01 (7). Lithium aluminium hydride (100 mg, 0.0026 mol) was suspended in anhydrous tetrahydrofuran (20ml) in an argon atmosphere. A solution of 3 (196mg, 0.00061mol) in anhydrous tetrahydrofuran (20 ml) was added dropwise at reflux temperature with stirring, and the mixture was refluxed for a further 1 h. After cooling, the excess of lithium aluminium hydride was decomposed with 0.1ml of water, 0.1ml of 15% sodium hydroxide solution and 0.5ml of water. The precipitated solids were removed by filtration and washed with chloroform. The filtrate and washings were combined, dried (MgS04) and concentrated under reduced pressure. The residue containing the mixture of 4 and 7 was separated by column chromatography on silica gel with elution by 10% v/v diethylamine-light petroleum, giving pure 7 as a white oil (55 mg, 28%). IR (CHCl,): 3600 cm-' (YOH), C Z ~ H ~ ~ N ~ O (324.45): found C 77.80, H 8.64, N 8.67%; calculated, C 77.73, H 8.70, N 8.64%.

Acknowledgements

The authors are grateful to Professor 0. P. Strausz for helpful discussions and to Dr A. Szollosy and Dr I. Pelczer for some 'H NMR spectra. One of us (G.T.) thanks the Natural Sciences and Engineering Research Council of Canada for a visiting fellowship (University of Alberta, Edmonton, Alberta, Canada).

686 G. TOTH ET AL.

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