Pergamon

0040-4039(94)02351-4

Tetrahedron Letters, Vol. 36, No. 5, pp. 681-682, 1995 Elsevier Science Ltd

Printed in Great Britain 0040-4039/95 $9.50+0.00

Synthesis of (+)-Plakoridine A Lactam

Jeffrey A. Stafford Department of Medicinal Chemistry

Glaxo Research Institute Five Moore Drive

Research Triangle Park, North Carolina 27709

Abstract: A stereocontrolled synthesis of plakoridine A lactam, a degradation product of the marine alkaloid plakoridine A, is described.

Recently Kobayashi and coworkers reported the isolation and structure determination of the marine

alkaloid plakoridine A (1), which they extracted from an Okinawan sponge of the genus Plakortis. 1 Plakoridine

A, whose structure was revealed largely by extensive NMR studies, contains a fully substituted, functionally

diverse pyrrolidine ring featuring an unprecedented union of tyramine, an apparent polypropionate unit, and a

fatty acid-derived side chain. As part of the structure elucidation of plakoridine A, the Japanese group subjected

1 to an ozonolysis in order to determine the length of the fatty acid chain. Mass spectrometry on the products

from this ozonolysis displayed two fragments corresponding to lactam 2 (m/z 321, M +) and to heptadecanoic

acid (m/z 270, M+). The intriguing structure of 1, as well as the finding that plakoridine A is cytotoxic against

the murine lymphoma L1210 cell line, prompted us to initiate its total synthesis. In this Letter we describe a

short, stereocontrolled synthesis of 2, which we have termed "plakoridine A lactam.'"

CH302C.~ ~ "-. OH O0 " .~ ,~CH302C" OH

OH3 ,, ~ CH3 C H 3 ~ 0

OH OH

Plakoridine A (1) 2

The synthesis of 2 is shown in the Scheme below. Dipolar cycloaddition 2 between nitrone 3, which is

derived by condensation of the corresponding N-hydroxytyramine with butyraldehyde, 3 and dimethyl maleate

(4) provided in 86% yield a mixture of isoxazolidines 5 and 6, which are epimeric at C5. The major isomer 6, 4

which is the product of endo cycloaddition, was treated with Raney nickel in methanol under 260 psi H2 to

afford a 2:3 mixture of the desired lactam 2 and lactam 7 in a combined 88% yield. Complete conversion of 7

to 2 was effected in 87% yield by resubmission of purified 7 to conditions of transfer hydrogenolysis (4~,

HCO2H:CH3OH, 1(1% Pd/C). Finally, the C3-C4-C5, trans-trans relative stereochemistry was established by a

1H NOESY experiment, which showed a significant NOE interaction between the C3 and C5 protons. 5

681

682

Scheme

0- I ~ J ' ' ' '%'' '~ N ~ CH3 CH302C~CO2CH3 toluene, 2 h +

BnO (86%) 3 4

C H3020. .0020H3 0H302 C . .0020H3 CH302C OH "~ ' : " 3 , ~ ~ N ": t. separation ~ , ~

C H 3 ~ ..... 2. Raney nickel N CH H2, CHaOH CH N 0

OBn OBn 0 R

5 (1 : 4) 6 4% HCO2H:CHaOH, ~ . 7: R = Bn; 10% Pd/C (87%) 2: R = H

In summary, we have developed an efficient synthesis of plakoridine A lactam (2) from nitrone 3 in

56% overall yield. Remaining efforts to complete the synthesis of plakoridine A by attachment of the fatty acid

side chain are underway and will be reported in due course. 6

References and Notes

1.

2.

3.

4.

5.

6.

Takeuchi, S.; Ishibashi, M.; Kobayashi, J. Jr. Org. Chem. 1994, 59, 3712.

For a recent review of nitrone cycloaddition chemistry, see: Confalone P. N.; Huie, E. M. Org. React.

1988, 36, 1.

Full details on the synthesis of 3 will be reported later. The 1H NMR data for 3 are as follows: (400

MHz, CDC13) ~ 0.86 (t, 3, J = 7.4), 1.41 (m, 2), 2.38 (m, 2), 3.15 (t, 2, J = 6.9), 3.90 (t, 2, J = 6.9), 5.04

(s, 2), 6.36 (t, 1, J = 5.8), 6.90 (d, 2, J = 8.5), 7.11 (d, 2, J = 8.5), 7.30-7.43 (m, 5).

tH NMR data for 6:(400 MHz, CDC13) 8 0.90 (t, 3, J = 7.2), 1.25-1.58 (m, 4), 2.86 (m, 1), 2.99-3.15

(m, 4), 3.41 (t, 1, J = 8.1), 3.69 (s, 3), 3.76 (s, 3), 4.71 (d, 1, J = 8.6), 5.04 (s, 2), 6.90 (d, 2, J = 8.6),

7.15 (d, 2, J = 8.6), 7.30-7.44 (m, 5).

Spectral data for lactam 2: IR (thin film): 3320, 1740, 1680, 1520, 830 cm-l; IH NMR: (400 MHz,

CDC13) ~ 0.95 (t, 3, J = 7.2), 1.23-1.33 (m, 2), 1.44-1.53 (m, 1), 1.73-1.82 (m, I), 2.63-2.70 (m, 1),

2.75-2.84 (m, 2), 3.07-3.13 (m, 1), 3.71 (dt, 1, J = 2.8, 7.8), 3.76 (s, 3), 3.92-3.99 (m, 1), 4.25 (bs, 1), 4.33 (d, 1, J = 8.2), 6.74 (d, 2, J = 8.2), 7.02 (d, 2, J = 82); 13C NMR: (100 MHz, CDC13) ~ 13.98,

16.91, 32.37, 34.05, 41.84, 51.26, 52.67, 56.37, 72.50, 115.56, 129.19, 129.76, 154.94, 172.81, 172.97;

FABMS: mlz 322 (M+H, 100%)% 202 [(M- CH2CH2C6H40)+H, 12%] +.

The author is grateful to Mr. Randy Rutkowske for performing the IH NOESY experiments on 6 and 2,

and to Drs. Paul Feldman and James Veal for insightful discussions.

(Received in USA 14 November 1994; accepted 1 December 1994)