1792 preparation of glycol 16. Hydrolysis of the intermediate osmate ester furnished 577 mg of crude material, which gave 243 mg of homogeneous, but amorphous, glycol on chromatography over Florisil. The glycol thus produced was dissolved in 5 ml of dry benzene and was treated directly with a solution of 384 mg of lead tetraacetate in 7 ml of anhydrous benzene. After 15 min at room temperature, the reaction mixture was worked up as previously described, yielding 214 mg of crystalline residue: : : :A 3.67, 5.80, and 5.94 1.1. Attempts to purify a small sample of the keto aldehyde 36 by chromatography (alumina) and subsequent crystallization from
methylene chloride-petroleum ether gave an isomer, mp 21 5216”, A“:, 2.81, 3.65, and 5.83 p, for which structure 37 is suggested. Anal. Calcd for G4H2604: C, 76.17; H, 6.92. Found: C, 76.23; H, 7.05. In view of this difficulty the remainder of the crude keto aldehyde above was reduced directly with lithium aluminum hydride in ether as described for the reduction of keto ester 33. Chromatography of the reduction product (Florisil) and crystallization from ethyl acetate-petroleum ether yielded a sample of glycol 34, mp 210.5-211.5”, that was indistinguishable from the specimen derived from keto ester 33.
Alkaloid Studies. LVI.’ The Constitution of Vallesiachotaminez Carl Djerassi, H. J. Monteiro, A. Walser, and L. J. Durham
Contribution f r o m the Department of Chemistry, Stanford University, Stanford, California. Received December 6, 1965 Abstract: Through a combination of chemical and spectroscopic techniques (notably nuclear magnetic resonance and mass spectrometry) it has been possible to show that vallesiachotamine, an alkaloid isolated from the Peruvian Apocynaceae Vallesia dichotoma Ruiz et Pav, possesses structure I. A likely biogenetic route to this unusual structure is discussed.
xtensive studies”6 in our laboratory on the constituents of the Peruvian plant Vallesia dichotoma Ruiz et Pav (family, Apocynaceae) have resulted in the isolation of 28 alkaloids, all but six of which have now been fully characterized. We should now like to report the structure elucidation of‘ one of the remaining alkaloids, present to the extent of approximately0.001%, which we have named vallesia~hotamine.~As will be shown below, its structure (I) is of unusual biogenetic interest. The very limited amount of material demanded great dependence upon physical measurements and establishment of empirical formulas principally through mass spectrometric measurements rather than combustion analyses. The alkaloid is relatively unstable to exposure to air and light, but this feature did not apply to some of its transformation products. The empirical formula C21H22N203 was established by high-resolution mass measurements and supported by the only combustion analysis6performed in this work. Its ultraviolet absorption spectrum (Figure l), though strongly suggestive of an indole, exhibited abnormally high extinction in the 290-mp region, which suggested the existence of a second chromophore absorbing in that region. The infrared spectrum exhibited bands at 2.89, 2.98, 6.02, and 6.25 p typical of NH or OH and of a,p-unsaturated carbonyl groupings. The mass spectrum (Figure 2)8
E
(1) For paper LV see R. R. Arndt and C. Djerassi, Experientiu, 21, 566 (1965). (2) Financial support from the National Institutes of Health (Grant No. GM-11309) of the U. S. Public Health Service is gratefully acknowledged. The purchase of the Atlas CH-4 mass spectrometer used in this investigation was made possible through NASA Grant NsG 81-60. (3) J. S . E. Holker, M. Cais, F. A. Hochstein, and C. Djerassi, J. Org. Chem., 24, 314 (1959). (4) K. S. Brown, Jr., H. Budzikiewicz, and C. Djerassi, Tetrahedron Lefters, 1731 (1963). ( 5 ) A. Walser and C. Djerassi, Helv. Chim. Acla, 47, 2073 (1964). (6) A. Walser and C. Djerassi, ibid., 48, 391 (1965). (7) This was earlier6 referred to as alkaloid number 20. (8) Empirical formulas are marked for those peaks where the composition was established by high-resolution mass measurements.
Journal of the American Chemical Society
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88:8
/ April 20,1966
displayed a pattern, which was unlike that of any of the various indole alkaloids hitherto in~estigated,~ but the high-resolution mass measurements did shed some light on the nature of the three oxygen atoms, which appeared to be incorporated in one carbonyl (see m / e 322 in Figure 2) and one methoxycarbonyl (see mle 291 and 263 in Figure 2) group. These conclusions were verified by the 100-Mc nmr spectrum, whose most salient features are summarized in Table I. The spectrum was complicated by the fact that most of the signals appeared in pairs presumably due to restricted rotation of one or more groups,5 but this did not preclude making the assignments summarized in Table I. Table I. Nmr Spectrum of Vallesiachotamine (I) NISU signal,’ 6 (ppm)
No. of protons
10.2/9.3 8,618.55 7.717.67
1 1 1
7.6-7.1 4 6,6516.55 1 (two quartets, J = 7.5 cps) 2,1812.07 3 (two doublets, J = 7.5 cps) 3.64 a
3
Assignment C (0F-H NH (indole)
>C=C-H Aromatic H CHsCH=C< CHaCH=C< COzCHs
Doubling of signals presumed to be due to restricted rotation.
As will be shown below, these conclusions could be verified by nmr studies (see Figure 3) on derivatives, which did not exhibit these complicating features. The analytical and spectral data cited so far can be summarized in terms of the following expression, which (9) H. Budzikiewicz, C. Djerassi, and D. H. Williams, “Structure Elucidation of Natural Products by Mass Spectrometry,” Vol. I, HoldenDay, Inc., San Francisco, Calif., 1964, Chapters 3-9.
4',3 Figure 2. Mass spectrum of vallesiachotamine (I). 3.01
tI I . 200
.
minum hydride product thus points toward the existence of a tetrahydro-P-carboline moiety in vallesiachotamine. 2% '
'
'
'
&rn#
wovoleqth-
Figure 1. Ultraviolet absorption spectra of vallesiachotamine (I), dihydrovallesiachotamine (IV), and lactone (VII). a (M-1)
prompted chemical experiments involving one or more of the carbonyl groups or double bonds.
b
184)
b' (,,/e 184)
a. a qCH N
/N+
N
I
R
+ "H
I
c (m/e 170)
d
(m/e
N
I
H
H
The first reaction attempted was lithium aluminum hydride reduction, which led to a complex mixture. By means of' thin layer chromatography, there was isolated one homogeneous, amorphous product (subsequently assigned structure VI), whose empirical formula (established by mass spectrometry) corresponded to the reduction of the two carbonyl groups of vallesiachotamine, an assumption which was supported by the complete absence of carbonyl absorption in the infrared. Most significant was the observation that the ultraviolet absorption spectrum was now completely typical of a simple 2,3-disubstituted indole. lo The abnormally high extinction of vallesiachotamine in the 290-mp region (Figure 1) must, therefore, be associated with one of the carbonyl groups. Due to the small amount of relatively insoluble product, only a poorly resolved nmr spectrum could be obtained, but the absence of any signal associated with an N-methyl function demonstrated that the formyl group of vallesiachotamine could not be attached to nitrogen. The mass spectrum of this lithium aluminum hydride reduction product was grossly different from that (Figure 2) of the parent alkaloid. While the base peak was still due to the molecular ion (m/e 324), the second most intense peak was now at m / e 323, and, aside from a strong peak at m/e 306 (M - HzO), the most diagnostic peaks were found at m / e 184, 169, 170, and 156. These four peaks, coupled with a strong M - 1 ion, have been shown earlierg,'la to be associated with a substituted tetrahydro-P-carboline system and have been attributed to structures a-e. The presence of these same peaks in the mass spectrum of the lithium alu-
(m/e
H
169)
1
CHz
e (m/e 156)
Experimentally, a much more satisfactory reduction of vallesiachotamine was achieved by means of sodium borohydride in ethanol solution, which proceeded in high yield to afford a crystalline dihydrovallesiachotamine (subsequently shown to be IV). The ultraviolet absorption spectrum (see Figure 1) was very similar to that of vallesiachotamine and the high extinction in the 290-mp range demonstrated that the carbonyl chromophore responsible for that absorption was still intact. The nmr spectrum (Figure 3) exhibited the same signals as the parent alkaloid (Table I) except for the absence of the lowest field signal associated with the aldehydic proton of vallesiachotamine and the presence of a new two-proton signal at 6 4.03 due to the grouping =CCHzO. Aside from the expected two mass unit shift of the molecular ion peak (as compared to Figure 2), the most significant feature of the mass spectrum of dihydrovallesiachotamine (IV) was the absence of an M - CO ion. This cumulative evidence, coupled with the diminished intensity of the infrared carbonyl absorption band, is only compatible with the presence of grouping A in vallesiachotamine (I), which has been transformed into B in dihydrovallesiachotamine (IV) upon reduction with sodium borohydride. Partial structure A is Finch, W. I. Taylor, H. Budzikiewicz, J. M. Wilson, and C. Djerassi. J . Am. Chem. Soc., 85, 1523 (1963). (b) One of the referees suggested the following mechanism for the generation of butyraldehyde.
I
(IO) Cf.A. W. Sangster and K. L. Stuart, Chem. Rev.,65, 69 (1965). (1 1) (a) L. D. Antonaccio, N. A. Pereira, B. Gilbert, H. Vorbrueggen, H. Budzikiewicz, 3. M. Wilson L. J. Durham, and C. Djerassi, J . Am. Chem. Soc., 84, 2161 (1962); see also G. Spiteller and M. SpitellerFriedmann, Monarsh., 93, 795 (1962); B. Gilbert, J. A. Brissolese, N.
1
H
Djerassi, Monteiro, Walser, Durham
I Constitution of Vallesiachotamine
1794
Figure 3. Nmr spectrum (100 Mc) of dihydrovallesiachotamine (IV).
further supported by the experimentally verified, though mechanistically obscure,llb isolation of nbutyraldehyde upon high-temperature pyrolysis of vallesiachotamine. H
1
1
CHS-C=C-CHO
H NaBHI
1
C2Hs
\
\
1
-+CHa--C=C-CHzOH
PtOn --f
EtOH
A
support from the observation that the related ethyl pdiethylaminocrotonate exhibits its principal ultraviolet absorption maximum at 288 mp. l 2
Hz
,N,-CH=C-CO,CH,
D
CH3
I
N-C=CHCOzCzHs / CZH5 x max 288 mg
I
B
CH~-CH~-CHCH~OH C
Microhydrogenation of dihydrovallesiachotamine (partial structure B) resulted in the uptake of I molar equiv of hydrogen and formation of tetrahydrovallesiachotamine (partial structure C ) as shown by the additional two mass unit shift of the molecular ion (m/e 354) and the unchanged character of the ultraviolet absorption spectrum. Attention should now be directed at the chromophoric system, which is responsible for the high ultraviolet absorption (Figure 1) of vallesiachotamine near 290 mp. It must incorporate the methoxycarbonyl function (still present in dihydrovallesiachotamine (IV) and tetrahydrovallesiachotamine (V), but absent in the lithium aluminum hydride reduction product VI) as well as the strongly deshielded olefinic proton, which is responsible for the sharp downfield singlet at 6 7.66 in the nmr spectra of vallesiachotamine (Table I) and dihydrovallesiachotamine (Figure 3). These properties taken together with the associated infrared 6.02 and 6.25 p ) and the inability of vallesidata (A, achotamine to form a methiodide are uniquely accommodated in partial structure D, which gains powerful Journal of the American Chemical Society
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1 April 20, 1966
E
Combination of moiety D with the previously discussed tetrahydro-p-carboline fragment leads to partial structure E, which together with A accounts for all of the atoms in vallesiachotamine except for one carbon and two hydrogen atoms. This extra carbon atom can be attached to E in only two ways, leading to expressions F and G. Attachment of the crotonaldehyde grouping (12) I
