Elaeocarpus Alkaloids. The Synthesis of dl-Elaeokanine-A and dl-Elaeokanine-C.

Joseph J. Tufariello* and Sk. Asrof Ali Department of Chemistry

State University of New York at Buffalo Buffalo, New York 14214

Abstract - The synthesis of dl-elaeokanine-A and dl-elaeokanine-C is

described by an approach which utilizes a nitrone cyclo-

addition to generate a B-aminoketone, which upon annulation

produces one or the other of the title alkaloids depending

upon conditions.

We wish to describe herein a synthetic entry into the Elaeocarpus family of alkaloids, a

relatively new class of indolizidine alkaloids isolated from the leaves of large, spreading

trees indigenous to New Guinea and India. "* Some of the more common members of this class of

alkaloids include elaeocarpine (&), isoelaeocarpine (2_), and isoelaeocarpicine (a), repre-

sentative of the aromatic Elaeocarpus alkaloids. The leaf alkaloids derived from Elaeocarpus

kaniensis Schltr., a large tree found in the rain-forests of New Guinea, contains none of the

more connnon indolizidine alkaloids (e.g., 1, 2, or 2). Instead, the less complex, but

3 4 5

obviously biogentically and chemically related, alkaloids elaeokanine-A (4) and elaeokanine-C

(3) are representative of the alkaloidal composition. 3

As part of our synthetic objective to construct a number of these systems with a

common synthetic design, we initially chose to attack the nonaromatic alkaloids

4445

4446 30. 46

elaeokanine-A (4) and elaeokanine-C (2). The stereochemical relationship of elaeokanine-C

and isoelaeocarpicine (3) suggested that a synthetic solution of the relative stereochemical

features of the former would suffice as well for the latter. The f+aminoketone moiety

apparent in each of these alkaloids suggested to us the use of nitrone precursors. Indeed, we envisioned that yet another B-aminoketone 2, (cf. Scheme 1) would serve as a common intermediate to the nonaromatic indolizidines. Thus, we have invoked the highly regio-

selective4 and stereoselective cycloaddition of I-pyrroline l-oxide ($) with 1-pentene

(1lO'C; sealed tube) to afford isoxazolidine 2, bp 82-84°C (5.5 mn), in 72% yield. The

isoxazolidine displays H-2 at 8 4.04 ppm (m, 1). The S-aminoalcohol g (90%) was readily

Scheme 1

l-i

+ -O/N+ 7 I>

MC 6 7

derived from Z by catalytic hydrogenolysis (10% Pd/C; H2). The desired, albeit thermally

labile, B-aminoketone 2 was obtained by Jones oxidation. This ketone, bp 53-54°C (0.07 mm),

was used directly without purification. When this crude 6-aminoketone was treated with

acrolein (1 equiv.) in benzene containing potassium t-butylate (3 equiv.), a chromatographi-

tally separable mixture (45%) of dl-elaeokanine-A (9) and an unsatured aldehyde (i.e., 11)

are formed in a 4:l ratio, respectively. The dl-elaeokanine-A (picrate mp 134-136°C) exhibits

strong carbonyl absorption at 1670 cm -' (IR; CC14) and displays NMR characteristics ((100 MHz,

CDC13) 6 0.92 (t, 3, J = 7 Hz), 1.1-2.0 (m, 5), 2.04-3.18 (m, 9), 3.44 (broad t, 1), and 6.82

ppm (m, 1)) identical to those of d-elaeokanine-A. lc

Aldehyde 11, picrate mp 169-171'C dec., the alternate (i.e. to 3) aldol product derived

xn. Lh

from An, exhibits its carbonyl stretch at 1660 cm-' (IR, neat) and shows absorption

EtOH) at 246 nm (e 11,930). Its NMR spectrum (100 MHz, CDC13) reveals the presence F;

4447

(UV; 95%

of the

aldehydo proton at 6 10.12 ppm (s, 1) and the C-5 equatorial proton" as a sharp doublet at 6

3.84 ppm (J = 16 Hz).

When the crude @aminoketone 2, derived from the Jones oxidation of B is exposed to

acrolein (1 equiv.) in methylene chloride, followed (after solvent removal) by concentrated

hydrochloric acid (2h, 25“(Z), there results a chromatographically separable mixture (44% from

2) of dl-elaeokanine-C and aldehyde 11, in a 3:1 ratio respectively. The elaeokanine-C. mp

69-70°C, exhibits IR (CC1 4; 3470 and 1710 cm-') and NMR (100 MHz, CDC13) behavior (6 0.88 (t,

3, J = 7.0 Hz), 1.0-3.2 (m, 16), 3.56 (broad s, 1, cont. dependent), and 4.16 ppm (q, 1, J =

2.2 Hz)) identical to that reported for the natural product.lc The magnitude of the coupling

constants observed for the equatorial H-7 proton supports the assigned configuration lc (cf.

w. Interestingly, we could not detect the C-7 epimer of 2 from the acid catalyzed aldol

cyclization.

We believe that elaeokanine-C (3) is the product of kinetic, rather than thermodynamic

control, since exposure of the synthetic alkaloid to concentrated hydrochloric acid for 2 h

at 25'C leaves it unaltered. An NMR examination of the product derived from this acid

treatment shows the absence of both aldehyde ii, a product which would be anticipated if the

aldol process were reversible, and elaeokanine-A. Indeed, the NMR spectrum so obtained is

virtually identical to that of the starting material. It is our belief that the arrival

H30+ a

I0 - - 5a

o&-Pr

at the transition state for the IQ + 2 process is facilitated by hydrogen bonding involving

the enolic hydroxyl function (cf., 10e) and the aldehyde carbonyl. The aldol closure of

19~ directly affords 2 with the correct relative stereochemistry at C-7, C-8, and C-9 (cf.

Z!). Indeed, such a stereospecific process may be involved in the biogenesis of these

alkaloids since the C-7 epimers of the Elaeocarpus alkaloids have not been reported.

AA48

Acknowledgement - We wish to thank the Institute of General Medical Sciences of the NIH for

financial assistance (GM 25303). Moreover, we are grateful to Dr. J. A. Lamberton (CSIRO,

Melbourne) for the NMR and IR spectra of natural d-elaeokanine-A and dl-elaeokanine-C, and

for IR (KBr) spectra of the methiodide of both natural and synthetic elaeokanine-C.

References and Notes

1.

2.

3.

4.

5.

6.

(a) S. R. Johns, J. A. Lamberton, A. A. Sioumois, and R. I. Willing, Aust. J. Chem., 22, 775 (1969); (b) S. R. Johns, J. A. Lamberton, A. A. Sioumis, H. Suares, and R. I. Willing, ibid., 24, 1679 (1971); (c) N, K. Hart, S. R. Johns, J. A. Lamberton, ibid-, 8Tf (1972).

A. K. Barua, C. Dasgupta, S. Chakravarti, M. K. Choudhury, and A. Ghosh, J. Indian Chem. Sot., 22, 531 (1976).

For previous synthetic efforts regarding these alkaloids, see ref. lc.

Sk. Asrof Ali, P. A. Senaratne, C. R. Illig, H. Meckler and J. J. Tufariello, Tetrahedron Lett., in press.

J. J. Tufariello and Sk. Asrof Ali, Tetrahedron Lett., 4647 (1978).

For a discussion of the spectral characteristics of related systems, see T. A. Crabb, R. F. Newton, and D. Jackson, Chem. Rev., Z_i, 109 (1971).

(Received in USA $0 Juljr 1979)