4914
J . Org. Chem. 1997, 62, 4914-4915
Asym m etr ic Syn th esis of
(2S,3S,8S,9S)-N-Boc ADDA: Ap p lica tion of
a P a lla d iu m (0)-Ca ta lyzed Cr oss-Cou p lin g
Rea ction of Tr isu bstitu ted Olefin s
J ames S. Panek* and Tao Hu
Department of Chemistry, Metcalf Center for Science and
Engineering, 590 Commonwealth Avenue, Boston
University, Boston, Massachusetts 02215
Received April 11, 1997
In the preceeding paper, we described the regio- and
stereocontrolled preparation of branched trisubstituted
conjugated dienes by a palladium(0)-catalyzed cross-
coupling reaction.1 Here, we report the convergent,
asymmetric synthesis of the C21 â-amino acid Adda
associated with the bioactive marine natural products
motuporin (1a )2 and nodularin (1b). Motuporin, recently
identified through an enzyme assay-guided screening of
crude extracts from the marine sponge Theonella swin-
hoei Gray,3 and the related agent nodularin, isolated from
the cyanophyte Nodularin spumigena,4 have displayed
potent inhibitory activity against a number of protein
phosphatases. Members of a related family of hepato-
toxic heptapeptides, the mycrocystins, have displayed
inhibitory activity against protein phosphatases.5 The
crucial biochemical role that the protein serine and
threonine phosphatases (PSPs) play in intracellular
signaling processes has generated much interest in the
ability of peptides bearing Adda to inhibit the activity of
these phosphatases.4 As a consequence, several research
groups have reported approaches to these natural prod-
ucts, and a number of syntheses of Adda and derivatives
have recently been published.5
F igu r e 1.
Sch em e 1
Our synthesis makes use of chiral allylsilane bond
construction methodology6 for the introduction of the four
stereogenic centers. The synthesis also features an
efficient palladium-catalyzed cross-coupling reaction for
the construction of the (E,E)-trisubstituted double bond.
The first disconnection at the C5-C6 bond produced two
subunits including the syn-homopropargylic ether (3,
C6-C10 subunit) and secondary allylic amine bearing
an (E)-vinyl iodide 4 (Figure 1). Further analysis of the
(1) Panek, J . S.; Hu, T. J . Org. Chem. 1997, 62, 4912.
(2) (a) Dilip de Silva, E.; Williams, D. E.; Anderson, R. J .; Klix, H.;
Holmes, C. F. B.; Allen, T. M. Tetrahedron Lett. 1992, 33, 1561-1564.
(b) Total synthesis of motuporin: Valentekovich, R. J .; Schreiber, S.
L. J . Am. Chem. Soc. 1995, 117, 9069-9070.
(3) (a) Rinehart, K. L.; Harada, K.; Namikoshi, M.; Chen, C.; Harvis,
C. A.; Munro, M. H. G.; Blunt, J . W.; Mulligan, P. E.; Beasley, V. R.;
Dahlem, A. M.; Carmichael, W. W. J . Am. Chem. Soc. 1988, 110, 8557-
8558. (b) Namikoshi, M.; Choi, B. W.; Sakai, R.; Sun, F.; Rinehart, K.
L.; Carmichael, W. W.; Evans, W. R.; Cruz, P.; Munro, M. H. G.; Blunt,
J . W. J . Org. Chem. 1994, 59, 2349-2357.
(4) (a) Goldberg, J .; Huang, H.; Kwon, Y.; Greengard, P.; Nairn, A.
C.; Kuriyan, J . Nature 1995, 376, 745-753 and references cited therein.
(b) Fujiki, H.; Suganuma, M. Adv. Cancer Res. 1993, 61, 143-194.
(5) (a) Namikoshi, M.; Rinehart, K. L.; Dahlem, A. M.; Beasley, V.
R.; Carmichael, W. W. Tetrahedron Lett. 1989, 30, 4349-4352. (b)
Chakraborty, T. K.; J oshi, S. P. Tetrahedron Lett. 1990, 31, 2043-
2046. (c) Beatty, M. F.; White, C. J .; Avery, M. A. J . Chem. Soc., Perkin
Trans. 1 1992, 1637-1641. (d) Kim, H. Y.; Toogood, P. L. Tetrahedron
Lett. 1996, 37, 2349-2352. (e) D’Aniello, F.; Mann, A.; Taddei, M. J .
Org. Chem. 1996, 61, 4870-4871. (f) Sin, N.; Kallmerten, J . Tetrahe-
dron Lett. 1996, 37, 5645-5648. (g) For the total synthesis of
microcystin, see: Humphrey, J . M.; Aggen, J . B.; Chamberlin, A. R. J .
Am. Chem. Soc. 1996, 118, 11759-11770.
(6) Masse, C. E.; Panek, J . S. Chem. Rev. 1995, 95, 1293-1316.
(7) Panek, J . S.; Beresis, R.; Xu, F.; Yang, M. J . Org. Chem. 1991,
56, 7341-7344.
(8) Panek, J . S.; Yang, M. G.; Solomon, J . J . Org. Chem. 1993, 58,
1003-1010.
(9) Panek, J . S.; Yang, M. J . Org. Chem. 1991, 56, 5755-5758.
(10) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 3769-3772.
(11) Satisfactory spectroscopic data (1H and 13C NMR, IR, CIMS,
CIHRMS) were obtained for all new compounds. Ratios of diastereo-
mers were determined by 400 Hz 1H NMR.
individual subunits produced two synthons in the form
of silane reagents 5 and 6, of which the anti-azido silane
6 was derived from (S)-5 through the azidation of â-silyl
enolate.7 Therefore, in the synthetic analysis, subunits
3 and 4 are ultimately derived from the same starting
silane 5.
C6-C10 Su bu n it. The preparation of this material
relied on the installation of the C8-C9 stereochemical
relationship through a syn-selective crotylation reaction.
This short sequence was initiated with a Lewis acid-
promoted condensation of silane (S)-58 with phenyl
acetaldehyde dimethyl acetal 7 (Scheme 1). In the
presence of BF3‚OEt2 (1.2 equiv), this syn-selective cro-
tylation (10:1 syn/ anti) proceeds through an open transi-
tion state involving an intermediate oxonium ion to give
the homoallylic ether 8 in 92% yield.9 Cleavage of the
trans-double bond of 8 by ozonolysis and direct dibro-
moolefination10 of the intermediate aldehyde gave the
desired acetylene precursor 9 in 88% yield (two steps).
Exposure of the dibromoolefin 9 to Corey-Fuchs condi-
tions (n-BuLi, THF, -78 °C) followed by trapping of the
intermediate acetylenic anion with MeI led to the methyl-
substituted acetylene 3 in 98% yield. This sequence
completed the synthesis of the C6-C10 subunit and
produced the material to be used in the cross-coupling
reaction.11
S0022-3263(97)00648-8 CCC: $14.00 © 1997 American Chemical Society