Asymmetric synthesis of (2S,3S,8S,9S)-N-Boc ADDA: Application of a palladium(0)-catalyzed cross-coupling reaction of trisubstituted olefins

Full text of DOI:10.1021/jo9706483

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

Communications
J . Org. Chem., Vol. 62, No. 15, 1997 4915
Sch em e 2
C1-C5 Su bu n it a n d N-Boc Ad d a . We were inter-
ested in the possibility of establishing the C3-nitrogen-
bearing stereocenter through a sequential diastereose-
lective crotylation and allylic azide isomerization reaction.
This option seemed quite attractive, given that literature
precedent for transformations of this type have been
established together with the notion that the use of the
allylic azide isomerization would provide access to a
stereochemically well-defined 1,3-azido alcohol. This
intermediate would serve as a precursor to the vinyl
iodide bearing the chiral secondary amine. The synthesis
of this subunit was initiated with a BF3‚OEt2-promoted
addition of the (S,R)-6 silane to an in situ generated
oxonium ion of formaldehyde derived from (S)-trioxane
10. The reaction afforded the azidofuran 11 as a single
diastereomer (>30:1, syn/ anti) in 91% yield (Scheme 2)
and installed the C2 Me-bearing stereocenter.12 The
isolation of the 2,5-cis tetrahydrofuran is consistent with
the stepwise mechanism proposed to rationalize the
formation of related tetrahydrofurans, cyclopentanes, and
∆2-isoxazolines; initial C-C bond construction occurs by
an anti-SE′ addition.6 The stabilized â-silyl carbocation
is illustrated as rearranging through a bridged carboca-
tion; this migration promotes the cyclization step, as it
proceeds with inversion at the C5 position.
Subsequent opening of the intermediate furan by
treatment with SbCl5 (1.3 equiv) followed by a suprafacial
allylic azide isomerization afforded the 1,3-azido alcohol
12 as a single diastereomer (96% overall yield).12 With
the establishment of an anti-stereochemical relationship
set between the methyl and azide groups, the 1,3-azido
alcohol was prepared for the Negishi-type coupling.1
Accordingly, the primary hydroxyl group was protected
as its TBS ether, the azide was reduced with SnCl2 in
anhydrous methanol (0 °C f rt, 4 h), and the primary
amine was then acylated with (Boc)2O in dioxane-
aqueous sodium bicarbonate13 to give the protected amine
13. This material was converted to the (E)-vinyl iodide
4 in two steps: ozonolysis of the double bond followed
by iodoolefination with iodoform (CHI3) in the presence
of CrCl2,14 which completed the preparation of the C1-
C5 subunit. The sequence installed the (E)-vinyl iodide
411 and defined the configuration of the double bond for
the palladium-catalyzed subunit coupling.
The coupling process was initiated with the regiose-
lective and stereospecific formation of the (E)-trisubsti-
tuted zirconate. The alkyne 3 was hydrozirconated using
the Schwartz reagent1 Cp2Zr(H)Cl (2.0 equiv, THF, 50
°C, 1.0 h) to produce the (E)-trisubstituted zirconate 14
as a single regioisomer.1 An in situ transmetalation with
anhydrous ZnCl2 (3.0 equiv, rt, 2.0 min) afforded the vinyl
zinc species 15. This material was used directly in the
subunit coupling with the (E)-vinyl iodide 4 in the
presence of Pd(Ph3P)4 (0.05 equiv, THF, rt, 5 min),
completing the assembly of the configurationally pure
(E,E)-diene in 84% yield.15 This one-pot sequence of
bimetallic mediated transformations gave the fully func-
tionalized Adda precursor 16, which was now set for final
conversion to N-Boc Adda. The following two-step depro-
tection/oxidation sequence was completed through the
intermediate amino alcohol derived from desilation with
fluoride ion. Treatment of a solution of the silyl ether
16 in THF with n-Bu4NF (1.0 equiv, THF, rt, 30 min)
resulted in clean conversion to the primary alcohol. This
material was oxidized to the carboxylic acid by treatment
with PDC (7.0 equiv, DMF, 22 h, 86%, two steps),
completing the synthesis of N-Boc Adda. Its spectro-
scopic and physical properties were identical in all
respects (1H, 13C, IR, [R]D, and MS) with those previously
reported.
In summary, the asymmetric synthesis of N-Boc Adda
was accomplished in a highly convergent manner using
11 steps in 27% overall yield. The synthesis and coupling
of the associated amino acids and completion of the total
synthesis of motuporin will be reported at a later time.
Ack n ow led gm en t. We are grateful to Professor
Peter Toogood (University of Michigan) for providing
(12) (a) Beresis, R. T.; Panek, J . S. Bioorg. Med. Chem. Lett. 1993,
13, 1609-1613. (b) Panek, J . S.; Yang, M.; Muler, I. J . Org. Chem.
1992, 57, 4063-4064.
1
copies of H and 13C NMR spectra of 2 for comparison.
Financial support was obtained from the NIH (RO1
CA56304).
(13) Evans, D. A.; Britton, T. C.; Ellman, J . A.; Dorow, R. L. J . Am.
Chem. Soc. 1990, 112, 4011-4030.
(14) Takai, K.; Nitta, K.; Utimoto, K. J . Am. Chem. Soc. 1986, 108,
7408-7410.
(15) Recently, French and Italian groups reported the synthesis of
Adda and that a similar Negishi-type coupling failed; see: D’Aniello,
F.; Mann, A.; Schonfelder, A.; Taddei, M. Tetrahedron 1997, 53, 1447-
1456.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedures and spectral data for all intermediates and the
final product (30 pages).
J O9706483